69 results on '"Alexis Nzila"'
Search Results
2. Concentration-Dependent Study of Nucleic Acid Blockers Used for Sequence-Specificity Enhancement in Nucleic Acids Detection
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Sulayman A. Oladepo, Basiru O. Yusuf, Alexis Nzila, Sankaran Saravanan, and Abdualilah Albaiz
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Multidisciplinary - Published
- 2022
3. Influence of Climatic Factors on the Abundance and Profusion of Mosquitoes in Eastern Province, Saudi Arabia
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Assad, Al-Thukair, Yasin, Jemal, and Alexis, Nzila
- Abstract
This study was performed to evaluate the change in seasonal abundance and distribution of individual mosquito vectors (Culex, Anopheles, and Aedes) in relation to the climatic factors in Eastern Province, Saudi Arabia, for the study period of 2014. The association between mosquito abundance and environmental parameters was investigated using bivariate and multivariate analysis. The study showed the range of temperature and relative humidity required for individual mosquito larvae abundance varies for Culex, Anopheles, and Aedes. However, no variation was observed in the range of temperature and relative humidity required for the abundance of adult Culex and Anopheles. The results revealed a negative relationship between mosquito larval/adult abundance and temperature (Total number of larva/adult is 671/11 in July, While it is 2462/221 in January). There is a link between relative humidity and rainfall, as the three climatic factors together were responsible for 33.1% (R2 = 0.331), 54.6% (R2 = 0.546), and 86.6% (R2 = 0.866) of the variance on Culex, Anopheles, and Aedes larvae, respectively. The effects of the three climatic parameters of temperature, relative humidity, and rainfall on mosquito larval and adult abundance were discussed. In addition, influences of other environmental factors on larval/adult mosquito distribution and abundance were also explained.
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- 2023
4. Biocatalytic asymmetric reduction of prochiral bulky-bulky ketones
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Auwal Eshi Sardauna, Muhammad Abdulrasheed, Alexis Nzila, and Musa M. Musa
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Process Chemistry and Technology ,Physical and Theoretical Chemistry ,Catalysis - Published
- 2023
5. Benzo[a]pyrene biodegradation by multiple and individual mesophilic bacteria in axenic conditions and in soil samples
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Alexis Nzila, Musa M. Musa, Emmanuel Afuecheta, Assad Thukair, Saravanan Sankaran, Lei Xiang, and Qing X. Li
- Abstract
Thus far, only a handful of bacterial strains that can independently degrade and utilize benzo[a]pyrene (BaP) as the sole carbon source have been isolated and characterized. Here, three new bacterial strains, JBZ1A, JBZ2B, and JBZ5E, were isolated from contaminated soil and, using 16S rRNA sequencing, were identified as Bradyrhizobium japonicum, Micrococcus luteus, and Bacillus cereus, respectively. The growth ability of each individual strain and a consortium of all strains in the presence of BaP (4–400 µmol·l−1, pH 7, 37°C) was identified by the doubling time (dt). The results illustrated that dt decreased with increasing BaP concentrations for individual strain and the consortium. The optimum growth conditions of the consortium were 37°C, 0.5% NaCl (w/v), and pH 7. Under these conditions, the degradation rate was 1.06 µmol·l−1·day−1, whereas that of individual strains ranged 0.9–0.38 µmol·l−1·day−1. B. cereus had the strongest contribution to the consortium’s activity, with a degradation rate of 0.9 µmol·l−1·day−1. The consortium could also remove BaP spiked with soil, but at a lower rate (0.01 µmol.l−1.day−1). High-performance liquid chromatography–high-resolution tandem mass spectrometry permitted the detection of the metabolites of these strains, and a biodegradation pathway has been proposed.
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- 2022
6. Benzo[A]Pyrene Biodegradation by Multiple and Individual Mesophilic Bacteria under Axenic Conditions and in Soil Samples
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Alexis Nzila, Musa M. Musa, Emmanuel Afuecheta, Assad Al-Thukair, Saravanan Sankaran, Lei Xiang, and Qing X. Li
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polyaromatic hydrocarbons ,bioremediation ,Health, Toxicology and Mutagenesis ,Public Health, Environmental and Occupational Health ,chromatography ,bacterial consortia ,mass spectrometry - Abstract
To date, only a handful of bacterial strains that can independently degrade and utilize benzo[a]pyrene (BaP) as the sole carbon source has been isolated and characterized. Here, three new bacterial strains—JBZ1A, JBZ2B, and JBZ5E—were isolated from contaminated soil and, using 16S rRNA sequencing, were identified as Brad rhizobium japonicum, Micrococcus luteus, and Bacillus cereus, respectively. The growth ability of each individual strain and a consortium of all strains in the presence of BaP (4–400 µmol·L−1, pH 7, 37 °C) was identified by the doubling time (dt). The results illustrate that dt decreased with increasing BaP concentrations for individual strains and the consortium. The optimum growth conditions of the consortium were 37 °C, 0.5% NaCl (w/v), and pH 7. Under these conditions, the degradation rate was 1.06 µmol·L−1·day−1, whereas that of individual strains ranged from 0.9 to 0.38 µmol·L−1·day−1. B. cereus had the strongest contribution to the consortium’s activity, with a degradation rate of 0.9 µmol·L−1·day−1. The consortium could also remove BaP spiked with soil but at a lower rate (0.01 µmol L−1.day−1). High-performance liquid chromatography–high-resolution tandem mass spectrometry permitted the detection of the metabolites of these strains, and a biodegradation pathway is proposed.
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- 2023
7. Current Knowledge and Future Challenges on Bacterial Degradation of the Highly Complex Petroleum Products Asphaltenes and Resins
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Alexis Nzila and Musa M. Musa
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Pollutant ,business.industry ,Bacterial degradation ,Pulp and paper industry ,asphaltenes ,biodegradation ,asphalt ,Environmental sciences ,chemistry.chemical_compound ,Petroleum product ,resins ,chemistry ,Asphalt ,Environmental science ,Petroleum ,Degradation (geology) ,GE1-350 ,Current (fluid) ,bacteria ,business ,bitumen ,General Environmental Science ,Asphaltene - Abstract
Petroleum products consist mainly of aliphatics, aromatics, asphaltenes and resins. After oil exploitation, the concentrations of asphaltenes and resins are high in oil reservoirs; however, they are also the petroleum pollutants most recalcitrant to degradation, leading to high oil viscosity. A sizable amount of work has been dedicated to understand the degradation mechanisms of aliphatics and aromatics; however, in comparison, little work has been carried out on asphaltene and resin degradation. This review discusses our current knowledge on the understanding of asphaltene and resin degradation. More specifically, it sheds light on work carried out to date on the degradation of these pollutants, and highlights the major gaps that limit our understanding of their degradation pathways. It also presents new potential research areas that can be explored to fill in these gaps.
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- 2021
8. Non-enzymatic detection of miR-21 in cancer cells using a homogeneous mix-and-read smart probe assay
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Sulayman A. Oladepo, Alexis Nzila, Abdulmalik Aminu, and Saravanan Sankaran
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MicroRNAs ,Neoplasms ,Biophysics ,MCF-7 Cells ,Oligonucleotides ,Humans ,Biological Assay ,Cell Biology ,Biosensing Techniques ,Molecular Biology ,Biochemistry - Abstract
We report a new assay system for the detection of miR-21 in cancer cells. The new assay works at room temperature and it does not involve enzymatic amplification. It consists a hairpin smart probe, designed to specifically recognize miR-21 target sequence. We tested the performance and sequence recognition capability of the smart probe to confirm desired specifications. We used the smart probe for the sequence-specific recognition of synthetic miR-21 oligonucleotides as well as mismatch sequences and we found that the probe recognizes the target sequence-specifically, while discriminating against mismatched sequences. We determined the limit of detection and limit of quantitation for the miR-21 oligonucleotides to be 1.72 nM and 5.78 nM, respectively, while the sensitivity is 6.90 × 10
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- 2021
9. Corrosion Inhibition of Rumex vesicarius Mediated Chitosan-AgNPs Composite for C1018 CS in CO2-Saturated 3.5% NaCl Medium under Static and Hydrodynamic Conditions
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Saviour A. Umoren, Moses M. Solomon, Alexis Nzila, and Ime B. Obot
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Renewable Energy, Sustainability and the Environment ,Geography, Planning and Development ,chitosan ,composite ,silver nanoparticles ,sweet corrosion ,corrosion inhibition ,Building and Construction ,Management, Monitoring, Policy and Law - Abstract
Rumex vesicarius (RVE) mediated chitosan–AgNPs composite was produced in situ by using an aqueous extract of Rumex vesicarius leaves as the reducing agent to reduce Ag+ to Ag0. The synthesized composite was evaluated as a sweet (CO2) corrosion inhibitor (CI) for C1018 carbon steel (CS) in 3.5 wt% NaCl solution under static and hydrodynamic conditions. The corrosion inhibitive performance was evaluated using electrochemical impedance spectroscopy (EIS), linear polarization resistance (LPR), and potentiodynamic polarization (PDP) techniques, as well as scanning electron microscopy (SEM)/energy dispersive X-ray spectroscopy (EDAX), and atomic force microscopy (AFM) on corroded C1018 CS without and with additives. The effect of concentration, immersion time, temperature, and rotation speed on the CI performance of the composite was also investigated. The corrosion inhibitive effect increased with increasing composite dosage, with the highest inhibition efficiency (IE) acquired at the maximum composite dosage of 0.3%. Beyond this concentration, the IE decline with increasing concentration. Furthermore, IE was found to increase with immersion time and decline with a temperature rise from 25 to 40 °C, with the optimum temperature of 60 °C found to accelerate corrosion without and with RVE-mediated Chi–AgNPs composite. Under high shear stress, the Chi–AgNPs composite exhibits moderate corrosion inhibition under hydrodynamic conditions. The surface analysis results validate the formation of a protective covering due to composite adsorption on the CS surface. The RVE-mediated chitosan–AgNPs composite could be recommended as a CI for C1018 CS in sweet (CO2) corrosion environments at ambient temperature.
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- 2022
10. An open dataset of
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Ambroise, Ahouidi, Mozam, Ali, Jacob, Almagro-Garcia, Alfred, Amambua-Ngwa, Chanaki, Amaratunga, Roberto, Amato, Lucas, Amenga-Etego, Ben, Andagalu, Tim J C, Anderson, Voahangy, Andrianaranjaka, Tobias, Apinjoh, Cristina, Ariani, Elizabeth A, Ashley, Sarah, Auburn, Gordon A, Awandare, Hampate, Ba, Vito, Baraka, Alyssa E, Barry, Philip, Bejon, Gwladys I, Bertin, Maciej F, Boni, Steffen, Borrmann, Teun, Bousema, Oralee, Branch, Peter C, Bull, George B J, Busby, Thanat, Chookajorn, Kesinee, Chotivanich, Antoine, Claessens, David, Conway, Alister, Craig, Umberto, D'Alessandro, Souleymane, Dama, Nicholas Pj, Day, Brigitte, Denis, Mahamadou, Diakite, Abdoulaye, Djimdé, Christiane, Dolecek, Arjen M, Dondorp, Chris, Drakeley, Eleanor, Drury, Patrick, Duffy, Diego F, Echeverry, Thomas G, Egwang, Berhanu, Erko, Rick M, Fairhurst, Abdul, Faiz, Caterina A, Fanello, Mark M, Fukuda, Dionicia, Gamboa, Anita, Ghansah, Lemu, Golassa, Sonia, Goncalves, William L, Hamilton, G L Abby, Harrison, Lee, Hart, Christa, Henrichs, Tran Tinh, Hien, Catherine A, Hill, Abraham, Hodgson, Christina, Hubbart, Mallika, Imwong, Deus S, Ishengoma, Scott A, Jackson, Chris G, Jacob, Ben, Jeffery, Anna E, Jeffreys, Kimberly J, Johnson, Dushyanth, Jyothi, Claire, Kamaliddin, Edwin, Kamau, Mihir, Kekre, Krzysztof, Kluczynski, Theerarat, Kochakarn, Abibatou, Konaté, Dominic P, Kwiatkowski, Myat Phone, Kyaw, Pharath, Lim, Chanthap, Lon, Kovana M, Loua, Oumou, Maïga-Ascofaré, Cinzia, Malangone, Magnus, Manske, Jutta, Marfurt, Kevin, Marsh, Mayfong, Mayxay, Alistair, Miles, Olivo, Miotto, Victor, Mobegi, Olugbenga A, Mokuolu, Jacqui, Montgomery, Ivo, Mueller, Paul N, Newton, Thuy, Nguyen, Thuy-Nhien, Nguyen, Harald, Noedl, Francois, Nosten, Rintis, Noviyanti, Alexis, Nzila, Lynette I, Ochola-Oyier, Harold, Ocholla, Abraham, Oduro, Irene, Omedo, Marie A, Onyamboko, Jean-Bosco, Ouedraogo, Kolapo, Oyebola, Richard D, Pearson, Norbert, Peshu, Aung Pyae, Phyo, Chris V, Plowe, Ric N, Price, Sasithon, Pukrittayakamee, Milijaona, Randrianarivelojosia, Julian C, Rayner, Pascal, Ringwald, Kirk A, Rockett, Katherine, Rowlands, Lastenia, Ruiz, David, Saunders, Alex, Shayo, Peter, Siba, Victoria J, Simpson, Jim, Stalker, Xin-Zhuan, Su, Colin, Sutherland, Shannon, Takala-Harrison, Livingstone, Tavul, Vandana, Thathy, Antoinette, Tshefu, Federica, Verra, Joseph, Vinetz, Thomas E, Wellems, Jason, Wendler, Nicholas J, White, Ian, Wright, William, Yavo, and Htut, Ye
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data resource ,drug resistance ,plasmodium falciparum ,parasitic diseases ,evolution ,malaria ,genomics ,rapid diagnostic test failure ,population genetics ,Articles ,genomic epidemiology ,Research Article - Abstract
MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum samples from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all samples showed genetic evidence of resistance to at least one antimalarial drug, and some samples from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.
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- 2021
11. Biogenic Synthesis and Characterization of Chitosan-CuO Nanocomposite and Evaluation of Antibacterial Activity against Gram-Positive and -Negative Bacteria
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Peace Saviour Umoren, Doga Kavaz, Alexis Nzila, Saravanan Sankaran Sankaran, and Saviour A. Umoren
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Polymers and Plastics ,General Chemistry ,chitosan ,copper oxide ,olive leaf extract ,nanocomposite ,antibacterial activity - Abstract
Chitosan-copper oxide (CHT-CuO) nanocomposite was synthesized using olive leaf extract (OLE) as reducing agent and CuSO4⋅5H2O as precursor. CHT-CuO nanocomposite was prepared using an in situ method in which OLE was added to a solution of chitosan and CuSO4⋅5H2O mixture in the ratio of 1:5 (v/v) and heated at a temperature of 90 °C. The obtained CHT-CuO nanocomposite was characterized using field emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), ultraviolet-visible (UV-Vis) spectrophotometry, energy-dispersive X-ray spectroscopy (EDAX), Fourier transform infrared spectroscopy (FTIR), and high-resolution transmission electron microscopy (TEM). TEM results indicated that CHT-CuO nanocomposite are spherical in shape with size ranging from 3.5 to 6.0 nm. Antibacterial activity of the synthesized nanocomposites was evaluated against Gram-positive (Bacillus cereus, Staphyloccous haemolytica and Micrococcus Luteus) and Gram-negative (Escherichia coli, Pseudomonas citronellolis, Pseudomonas aeruginosa, kliebisella sp., Bradyrhizobium japonicum and Ralstonia pickettii) species by cup platting or disc diffusion method. Overall, against all tested bacterial strains, the diameters of the inhibition zone of the three nanocomposites fell between 6 and 24 mm, and the order of the antimicrobial activity was as follows: CuO-1.0 > CuO-0.5 > CuO-2.0. The reference antibiotic amoxicillin and ciprofloxacin showed greater activity based on the diameter of zones of inhibition (between 15–32 mm) except for S. heamolytica and P. citronellolis bacteria strains. The nanocomposites MIC/MBC were between 0.1 and 0.01% against all tested bacteria, except S. heamolityca (>0.1%). Based on MIC/MBC values, CuO-0.5 and CuO-1.0 were more active than CuO-2.0, in line with the observations from the disc diffusion experiment. The findings indicate that these nanocomposites are efficacious against bacteria; however, Gram-positive bacteria were less susceptible. The synthesized CHT-CuO nanocomposite shows promising antimicrobial activities and could be utilized as an antibacterial agent in packaging and medical applications.
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- 2022
12. Biodegradation of selected hydrocarbons by novel bacterial strains isolated from contaminated Arabian Gulf sediment
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Alexis Nzila, Assad A. Al-Thukair, and Karim Malik
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0301 basic medicine ,Aquatic Organisms ,Geologic Sediments ,Science ,Oceans and Seas ,010501 environmental sciences ,Naphthalenes ,01 natural sciences ,Microbiology ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Petroleum Pollution ,0105 earth and related environmental sciences ,Naphthalene ,chemistry.chemical_classification ,Multidisciplinary ,biology ,Bacteria ,Biodegradation ,biology.organism_classification ,Proteus mirabilis ,Environmental sciences ,030104 developmental biology ,Hydrocarbon ,Biodegradation, Environmental ,chemistry ,Brevibacillus brevis ,Environmental chemistry ,Pyrene ,Medicine ,Rhodococcus - Abstract
Three strains of novel bacteria were isolated from oil-contaminated sediment from the Arabian Gulf (Brevibacillus brevis T2C2008, Proteus mirabilis T2A12001, and Rhodococcus quinshengi TA13008). The isolated strains were tested for their degrading efficacy of low and high molecular hydrocarbon (naphthalene and pyrene). The efficacy of the two-hydrocarbon degradation by the isolates bacterial was determined at a temperature of 25 °C and 37 °C and pH of 5.0 and 9.0. In inoculated media at 37 °C, Rhodococcus qinshengi fully metabolized naphthalene and degrade 56% of pyrene. Brevibacillus brevis break down over 80% of naphthalene at room temperatures (25 °C). However, it was found that P. mirabilis and R. qinshengi biodegraded nearly 94% of naphthalene in the incubated media. The capacity for pyrene and naphthalene degradation in varying pH and temperature conditions was shown to be significant in Rhodococcus qinshengi because of its mineralization exceeding 50% across the tested pH and temperature. This implies that the isolated strains are ideal for biodegradation of contaminated sediment with naphthalene and pyrene.
- Published
- 2020
13. Genetic alteration of ferredoxin NADP+-reductase or cysteine desulfurase in piperaquine-resistant Plasmodium berghei restores susceptibility to lumefantrine and abolishes the impact of probenecid, verapamil, and cyproheptadine
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Simplice Damintoti Karou, Loise Ndung'u, Beatrice Irungu, Francis Kimani, Daniel Kiboi, Fagdéba David Bara, Gabriel Magoma, Alexis Nzila, Peter Mwitari, Noah Machuki Onchieku, and Damaris Matoke-Muhia
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biology ,Chemistry ,Plasmodium falciparum ,Pharmacology ,Cyproheptadine ,biology.organism_classification ,Probenecid ,Piperaquine ,parasitic diseases ,medicine ,Verapamil ,Plasmodium berghei ,Artemisinin ,Ferredoxin—NADP(+) reductase ,medicine.drug - Abstract
The ability of the human malaria parasite, Plasmodium falciparum to develop resistance against mainstay drugs remains a public health problem. Currently, the antimalarial drugs, lumefantrine (LM), and piperaquine (PQ) are essential components of the mainstay artemisinin-based therapies used for the treatment of malaria globally. Here, we used a model parasite Plasmodium berghei, to investigate the mechanisms of LM and PQ resistance. We employed known resistance reversing agents (RA): probenecid, verapamil, or cyproheptadine to study the mechanisms of LM and PQ resistance in the standard 4-day suppressive test. We then employed reverse genetics to assess the impact of deleting or over-expressing plausible genes associated with the metabolism and transport of drugs. We show that only, cyproheptadine at 5mgkg-1 restored LM activity by above 65% against LM-resistant parasites (LMr) but failed to reinstate PQ activity against PQ-resistant parasites (PQr). Whereas the PQr had lost significant susceptibility to LM, the three RA, cyproheptadine verapamil, and probenecid restored LM potency by above 70%, 60%, and 55% respectively against the PQr. We thus focused on the mechanisms of LM resistance in PQr. Here we show the partial deletion of the cysteine desulfurase (SUFS) and overexpression of the Ferredoxin NADP+ reductase (FNR) genes in the PQr parasite achieved two results; i) abolished the impact of RA on LM activity; ii) restored the susceptibility of PQr to LM alone. Our findings associated SUFS and FNR protein with the action of LM and RA action in P. berghei. We demonstrate that the incorporation of any of the RA into an antimalarial combination that comprises LM would augment LM activity and concomitantly antagonize the emergence of LM resistance derived from PQ pressure. The impact of RA, deletion of SUFS, and overexpression of FNR on LM activity need to be tested in Plasmodium falciparum.nnAuthor summaryLumefantrine (LM) and piperaquine (PQ) are essential drugs for the treatment of malaria globally. Here, we used Plasmodium berghei, a model parasite that infects rodents to study how parasites escape killing by PQ and LM. We first used a second drug: probenecid, verapamil, or cyproheptadine to enhance the activity of LM or PQ. We show that cyproheptadine restores LM activity against LM-resistant parasites (LMr) but failed to reestablish PQ activity against PQ-resistant parasites (PQr). Since PQr is resistant to LM, combining LM with either cyproheptadine, verapamil, or probenecid reinstates LM activity against PQr. We then focused mainly on LM resistance in PQr. After genetically manipulating the PQr, we reveal that cysteine desulfurase (SUFS) and ferredoxin NADP+reductase (FNR) regulate LM capacity to kill parasites. Decreasing the level of SUFS or increasing FNR levels in the PQr makes the parasites susceptible to LM but abolishes the impact of probenecid, verapamil, and cyproheptadine on LM activity. Overall, we provide clues on the link between SUFS and FNR in the action of LM and RA in P. berghei. This study provides a basis for an in-depth analysis of how LM mediates parasites kill and how the parasite escapes LM action in Plasmodium falciparum.
- Published
- 2019
14. Pyrene biodegradation and proteomic analysis in Achromobacter xylosoxidans, PY4 strain
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Saravanan Sankara, Camila A. Ortega Ramirez, Qing X. Li, Musa M. Musa, Alexis Nzila, and Chanbasha Basheer
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0301 basic medicine ,Anthracene ,biology ,Achromobacter xylosoxidans ,010501 environmental sciences ,Biodegradation ,Phenanthrene ,biology.organism_classification ,01 natural sciences ,Microbiology ,Biomaterials ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,Biochemistry ,chemistry ,Dioxygenase ,Pyrene ,Waste Management and Disposal ,0105 earth and related environmental sciences ,Homogentisate 1,2-dioxygenase ,Naphthalene - Abstract
Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants from incomplete combustion and petroleum products. As the molecular weight increases, PAHs become more recalcitrant to biodegradation. A bacterial strain capable of metabolizing the four fused aromatic ring PAH pyrene was isolated and characterized. The analysis of 16S rRNA gene revealed that it belongs to Achromobacter xylosoxidans species. A. xylosoxidans PY4 can utilize pyrene as the sole source of carbon. PY4 has a doubling time (dt) of less than 1 day when it grows in the presence of 1–5 mg l−1 pyrene, a dt range similar to that of the most efficient pyrene biodegrading bacteria described so far. The optimal pyrene degradation conditions are at pH 7–9, 37–40 °C, and 0–2.5% NaCl. PY4 also utilizes salicylic acid, catechol, naphthalene, anthracene and phenanthrene. PY4 degrades more than 50% of 100 mg l−1 of pyrene, within the first 15 days, at a rate of 0.069 day−1, R2 = 0.99. The metabolites include monohydroxypyrene, 1-methoxyl-2-H-benzo[h]chromene-2-carboxylic acid, 9,10-phenanthrenequinone, 1-methoxyl-trans-2′-carboxybenzalpyruvate, and dibutyl-phthalate. Up-expressed proteins in response to pyrene are involved in cell homeostasis, genetic information synthesis and storage, and chemical stress. Among these proteins are 4-hydroxyphenylpyruvate dioxygenase and homogentisate 1,2-dioxygenase, involved in the lower pyrene degradation pathway.
- Published
- 2018
15. Degradation of benzo[a]pyrene by halophilic bacterial strain Staphylococcus haemoliticus strain 10SBZ1A
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Musa M. Musa, Lei Xiang, Qing X. Li, Marwan Al-Momani, Saravanan Sankara, and Alexis Nzila
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Salinity ,Staphylococcus ,Bacterial growth ,Pathology and Laboratory Medicine ,Physical Chemistry ,Biochemistry ,chemistry.chemical_compound ,Microbial Physiology ,Metabolites ,Medicine and Health Sciences ,polycyclic compounds ,Soil Pollutants ,Food science ,Materials ,Soil Microbiology ,Multidisciplinary ,Strain (chemistry) ,Organic Compounds ,Microbial Growth and Development ,Bacterial Pathogens ,Chemistry ,Biodegradation, Environmental ,Petroleum ,Benzo(a)pyrene ,Medical Microbiology ,Physical Sciences ,Medicine ,Pyrene ,Metabolic Pathways ,Pathogens ,Organic Materials ,Soil microbiology ,Research Article ,Science ,Materials Science ,Context (language use) ,Naphthalenes ,Microbiology ,complex mixtures ,Extremophiles ,Microbial Pathogens ,Bacteria ,Bacterial Growth ,Organic Chemistry ,Organisms ,Chemical Compounds ,Biology and Life Sciences ,Biodegradation ,Phenanthrene ,Staphylococcus haemolyticus ,Metabolism ,Chemical Properties ,chemistry ,Water Pollutants, Chemical ,Developmental Biology - Abstract
The exploitation of petroleum oil generates a considerable amount of “produced water or petroleum waste effluent (PWE)” that is contaminated with polycyclic aromatic hydrocarbons (PAHs), including Benzo[a]pyrene (BaP). PWE is characterised by its high salinity, which can be as high as 30% NaCl, thus the exploitation of biodegradation to remove PAHs necessitates the use of active halophilic microbes. The strain 10SBZ1A was isolated from oil contaminated soils, by enrichment experiment in medium containing 10% NaCl (w/v). Homology analyses of 16S rRNA sequences identified 10SBZ1A as a Staphylococcus haemoliticus species, based on 99.99% homology (NCBI, accession number GI: MN388897). The strain could grow in the presence of 4–200 μmol l-1 of BaP as the sole source of carbon, with a doubling time of 17–42 h. This strain optimum conditions for growth were 37 oC, 10% NaCl (w/v) and pH 7, and under these conditions, it degraded BaP at a rate of 0.8 μmol l-1 per day. The strain 10SBZ1A actively degraded PAHs of lower molecular weights than that of BaP, including pyrene, phenanthrene, anthracene. This strain was also capable of removing 80% of BaP in the context of soil spiked with BaP (10 μmol l-1 in 100 g of soil) within 30 days. Finally, a metabolic pathway of BaP was proposed, based on the identified metabolites using liquid chromatography-high resolution tandem mass spectrometry. To the best of our knowledge, this is the first report of a halophilic BaP degrading bacterial strain at salinity > 5% NaCl.
- Published
- 2021
16. Isolation and characterization of naphthalene biodegrading Methylobacterium radiotolerans bacterium from the eastern coastline of the Kingdom of Saudi Arabia
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Alexis Nzila, Saravanan Sankara, Assad Thukair, Musa M. Musa, and Basheer Chanbasha
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0301 basic medicine ,Soil bacteria ,Polluted soils ,030106 microbiology ,Industrial chemistry ,General Medicine ,010501 environmental sciences ,Biology ,Isolation (microbiology) ,biology.organism_classification ,01 natural sciences ,03 medical and health sciences ,Methylobacterium radiotolerans ,Botany ,Bacteria ,0105 earth and related environmental sciences - Abstract
Bioremediation is based on microorganisms able to use pollutants either as a source of carbon or in co-metabolism, and is a promising strategy in cleaning the environment. Using soil contaminated with petroleum products from an industrial area in Saudi Arabia (Jubail), and after enrichment with the polycyclic aromatic hydrocarbon (PAH) naphthalene, a Methylobacterium radiotolerans strain (N7A0) was isolated that can grow in the presence of naphthalene as the sole source of carbon. M. radiotolerans is known to be resistant to gamma radiation, and this is the first documented report of a strain of this bacterium using a PAH as the sole source of carbon. The commonly reported Pseudomonas aeruginosa (strain N7B1) that biodegrades naphthalene was also identified, and gas chromatography analyses have shown that the biodegradation of naphthalene by M. radiotolerans and P. aeruginosa did follow both the salicylate and phthalate pathways.
- Published
- 2016
17. Characterization of aerobic oil and grease-degrading bacteria in wastewater
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Saravanan Sankara, Assad Thukair, Alexis Nzila, and Shaikh A. Razzak
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0106 biological sciences ,Microbial Consortia ,Pseudomonas libanensis ,Wastewater ,010501 environmental sciences ,01 natural sciences ,chemistry.chemical_compound ,RNA, Ribosomal, 16S ,010608 biotechnology ,Glycerol ,Environmental Chemistry ,Food science ,Waste Management and Disposal ,0105 earth and related environmental sciences ,Water Science and Technology ,Bacteria ,biology ,Sphingobacterium ,Chemistry ,Chemical oxygen demand ,General Medicine ,Biodegradation ,biology.organism_classification ,Hydrocarbons ,RNA, Bacterial ,Biodegradation, Environmental ,Petroleum ,Biochemistry ,Pseudomonas poae - Abstract
A bacterial consortium that degrades cooking oil (CO) has been isolated in wastewater (WW) samples, by enrichment in olive CO. This consortium could degrade 90% of CO within 7-9 days (from an initial 1% [w/v]), and it is more active at alkaline conditions. The 16S ribonucleic acid (RNA) gene analysis showed that it contains five bacterium species: Stenotrophomonas rhizophila, Sphingobacterium sp., Pseudomonas libanensis, Pseudomonas poae and Pseudomonas aeruginosa. This consortium can degrade the free fatty acids (FFA): palmitic, stearic, oleic, linoleic and linolenic acids; glycerol, glucose and amylose; and albumin, but could not efficiently degrade carboxymethyl-cellulose. Each strain could also degrade CO and FFAs. The level of bacterial crude-activity of extracellular lipases was found to be between 0.2 and 4U/ml. Using synthetic WW, the consortium could reduce 80% of the chemical oxygen demand [from 10550 ± 2828 mg/l], 80% of nitrogen (from 410 ± 78 mgl/l) and 57% of phosphorus (from 93 ± 25 mg/l). Thus, this consortium can be utilized in the removal of CO from WW.
- Published
- 2016
18. Biodegradation of high-molecular-weight polycyclic aromatic hydrocarbons under anaerobic conditions: Overview of studies, proposed pathways and future perspectives
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Alexis Nzila
- Subjects
0301 basic medicine ,Health, Toxicology and Mutagenesis ,Microorganism ,Microbial Consortia ,010501 environmental sciences ,Toxicology ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Denitrifying bacteria ,Bacteria, Anaerobic ,Bioreactors ,Anaerobiosis ,Sulfate-reducing bacteria ,Polycyclic Aromatic Hydrocarbons ,0105 earth and related environmental sciences ,Naphthalene ,chemistry.chemical_classification ,food and beverages ,Aromaticity ,General Medicine ,Biodegradation ,Electron acceptor ,Pollution ,Anoxic waters ,Molecular Weight ,030104 developmental biology ,Biodegradation, Environmental ,chemistry ,Environmental chemistry ,Denitrification ,Environmental Pollutants - Abstract
The biodegradation of low- and high-molecular-weight polycyclic aromatic hydrocarbons (PAHs) (LWM-PAHs and HMW-PAHs, respectively) has been studied extensively under aerobic conditions. Molecular O2 plays 2 critical roles in this biodegradation process. O2 activates the aromatic rings through hydroxylation prior to ring opening and serves as a terminal electron acceptor (TEA). However, several microorganisms have devised ways of activating aromatic rings, leading to ring opening (and thus biodegradation) when TEAs other than O2 are used (under anoxic conditions). These microorganisms belong to the sulfate-, nitrate-, and metal-ion-reducing bacteria and the methanogens. Although the anaerobic biodegradation of monocyclic aromatic hydrocarbons and LWM-PAH naphthalene have been studied, little information is available about the biodegradation of HMW-PAHs. This manuscript reviews studies of the anaerobic biodegradation of HMW-PAHs and identifies gaps that limit both our understanding and the efficiency of this biodegradation process. Strategies that can be employed to overcome these limitations are also discussed.
- Published
- 2018
19. Piperaquine and Lumefantrine resistance in Plasmodium berghei ANKA associated with increased expression of Ca2+/H+ antiporter and glutathione associated enzymes
- Author
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Luna Kamau, Alexis Nzila, Daniel Kiboi, Beatrice Irungu, Lynette Isabella Ochola-Oyier, Jennifer Orwa, and Joseph K. Ng’ang’a
- Subjects
Male ,Plasmodium berghei ,Antiporter ,Immunology ,Real-Time Polymerase Chain Reaction ,Lumefantrine ,Article ,Antiporters ,Gene Expression Regulation, Enzymologic ,Antimalarials ,Mice ,chemistry.chemical_compound ,Parasitic Sensitivity Tests ,Piperaquine ,parasitic diseases ,Animals ,Coding region ,Cloning, Molecular ,Cation Transport Proteins ,Gene ,Glutathione Transferase ,Genetics ,Fluorenes ,Glutathione Peroxidase ,biology ,Plasmodium falciparum ,Sequence Analysis, DNA ,General Medicine ,Glutathione ,DNA, Protozoan ,biology.organism_classification ,Molecular biology ,Drug Resistance, Multiple ,Glutathione Reductase ,Infectious Diseases ,chemistry ,Ethanolamines ,Quinolines ,Parasitology - Abstract
We investigated the mechanisms of resistance of two antimalarial drugs piperaquine (PQ) and lumefantrine (LM) using the rodent parasite Plasmodium berghei as a surrogate of the human parasite, Plasmodium falciparum. We analyzed the whole coding sequence of Plasmodium berghei chloroquine resistance transporter (Pbcrt) and Plasmodium berghei multidrug resistance gene 1(Pbmdr-1) for polymorphisms. These genes are associated with quinoline resistance in Plasmodium falciparum. No polymorphic changes were detected in the coding sequences of Pbcrt and Pbmdr1 or in the mRNA transcript levels of Pbmdr1. However, our data demonstrated that PQ and LM resistance is achieved by multiple mechanisms that include elevated mRNA transcript levels of V-type H+ pumping pyrophosphatase (vp2), Ca2+/H+ antiporter (vcx1), gamma glutamylcysteine synthetase (ggcs) and glutathione-S-transferase (gst) genes, mechanisms also known to contribute to chloroquine resistance in P. falciparum and rodent malaria parasites. The increase in ggcs and gst transcript levels was accompanied by high glutathione (GSH) levels and elevated activity of glutathione-S-transferase (GST) enzyme. Taken together, these results demonstrate that Pbcrt and Pbmdr1 are not associated with PQ and LM resistance in P. berghei ANKA, while vp2, vcx1, ggcs and gst may mediate resistance directly or modulate functional mutations in other unknown genes.
- Published
- 2014
20. Amodiaquine resistance in
- Author
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Loise, Ndung'u, Benard, Langat, Esther, Magiri, Joseph, Ng'ang'a, Beatrice, Irungu, Alexis, Nzila, and Daniel, Kiboi
- Subjects
Plasmodium berghei ,parasitic diseases ,Resistance ,Amodiaquine ,Parasitology ,Cross-resistance ,Articles ,Drug Discovery & Design ,Research Article ,Malaria - Abstract
Background: The human malaria parasite Plasmodium falciparum has evolved drug evasion mechanisms to all available antimalarials. The combination of amodiaquine-artesunate is among the drug of choice for treatment of uncomplicated malaria. In this combination, a short-acting, artesunate is partnered with long-acting, amodiaquine for which resistance may emerge rapidly especially in high transmission settings. Here, we used a rodent malaria parasite Plasmodium berghei ANKA as a surrogate of P. falciparum to investigate the mechanisms of amodiaquine resistance. Methods: We used the ramp up approach to select amodiaquine resistance. We then employed the 4-Day Suppressive Test to measure the resistance level and determine the cross-resistance profiles. Finally, we genotyped the resistant parasite by PCR amplification, sequencing and relative quantitation of mRNA transcript of targeted genes. Results: Submission of the parasite to amodiaquine pressure yielded resistant line within thirty-six passages. The effective doses that reduced 90% of parasitaemia (ED 90) of the sensitive and resistant lines were 4.29mg/kg and 19.13mg/kg respectively. The selected parasite retained resistance after ten passage cycles in the absence of the drug and freezing at -80ºC for one month with ED 90 of 20.34mg/kg and 18.22mg/kg. The parasite lost susceptibility to chloroquine by (6-fold), artemether (10-fold), primaquine (5-fold), piperaquine (2-fold) and lumefantrine (3-fold). Sequence analysis of Plasmodium berghei chloroquine-resistant transporter revealed His95Pro mutation. We found no variation in the nucleotide sequences of Plasmodium berghei multidrug resistance gene-1 (Pbmdr1), Plasmodium berghei deubiquitinating enzyme-1 or Plasmodium berghei Kelch13 domain. However, high mRNA transcripts of essential transporters; Pbmdr1, V-type/H+ pumping pyrophosphatase-2 and sodium hydrogen ion exchanger-1 and Ca 2+/H + antiporter accompanies amodiaquine resistance. Conclusions: The selection of amodiaquine resistance yielded stable “multidrug-resistant’’ parasites and thus may be used to study shared resistance mechanisms associated with other antimalarial drugs. Genome-wide analysis of the parasite may elucidate other functionally relevant genes controlling AQ resistance in P. berghei.
- Published
- 2017
21. Whole-Genome Scans Provide Evidence of Adaptive Evolution in Malawian Plasmodium falciparum Isolates
- Author
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Kevin Marsh, Abdoulaye A. Djimde, Jacqui Montgomery, Issaka Zongo, Mark D. Preston, Alexis Nzila, Harold Ocholla, Susana Campino, Ogobara K. Doumbo, Alister Craig, Dominic P. Kwiatkowski, Anja T. R. Jensen, Daniel Alcock, Samuel Assefa, Jean Bosco Oudraogo, Steffen Borrmann, Mwapatsa Mipando, Rick M. Fairhurst, François Nosten, Tim J. Anderson, Taane G. Clark, Bronwyn MacInnis, and Anja Terlouw
- Subjects
Male ,Malawi ,Linkage disequilibrium ,genetic epidemiology ,Plasmodium falciparum ,Population ,Adaptation, Biological ,Population genetics ,wa_395 ,Evolution, Molecular ,Major Articles and Brief Reports ,Antimalarials ,parasitic diseases ,Genetic variation ,medicine ,Humans ,Immunology and Allergy ,Parasites ,Malaria, Falciparum ,Selection, Genetic ,Child ,education ,Allele frequency ,Genetics ,Molecular Epidemiology ,Genetic diversity ,education.field_of_study ,biology ,Genetic Variation ,Sequence Analysis, DNA ,medicine.disease ,biology.organism_classification ,3. Good health ,ws_300 ,Infectious Diseases ,qx_135 ,Child, Preschool ,qu_550 ,Female ,qu_470 ,genomes ,Genome, Protozoan ,Malaria - Abstract
BACKGROUND\ud Selection by host immunity and antimalarial drugs has driven extensive adaptive evolution in Plasmodium falciparum, and continues to produce ever-changing landscapes of genetic variation.\ud \ud METHODS\ud We carried out whole-genome sequencing of 69 P. falciparum isolates from Malawi and used population genetics approaches to investigate genetic diversity and population structure, and identify loci under selection.\ud \ud RESULTS\ud High genetic diversity (π=2.4 x 10(-4)), moderately high multiplicity of infection (2.7), and low linkage disequilibrium (500-bp) were observed in Chikhwawa District, Malawi, an area of high malaria transmission. Allele frequency-based tests provided evidence of recent population growth in Malawi and detected potential targets of host immunity and candidate vaccine antigens. Comparing the sequence variation between isolates from Malawi and those from 5 geographically dispersed countries (Kenya, Burkina Faso, Mali, Cambodia, and Thailand) detected population genetic differences between Africa and Asia, within Southeast Asia, and within Africa. Applying haplotype-based tests of selection to sequence data from all 6 populations identified signals of directional selection at known drug-resistance loci, including pfcrt, pfdhps, pfmdr1, and pfgch1.\ud \ud CONCLUSIONS\ud The sequence variations observed at drug-resistance loci reflect differences in each country's historical use of antimalarial drugs, and may be useful in formulating local malaria treatment guidelines.
- Published
- 2014
22. Mini review: Update on bioaugmentation in anaerobic processes for biogas production
- Author
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Alexis Nzila
- Subjects
Bioaugmentation ,Biochemical Phenomena ,020209 energy ,02 engineering and technology ,010501 environmental sciences ,01 natural sciences ,Microbiology ,chemistry.chemical_compound ,Nitrate ,Biogas ,0202 electrical engineering, electronic engineering, information engineering ,Bioreactor ,Anaerobiosis ,0105 earth and related environmental sciences ,business.industry ,Biodegradation ,Pulp and paper industry ,Renewable energy ,Anaerobic digestion ,Infectious Diseases ,chemistry ,Biofuels ,Fermentation ,Environmental science ,business ,Anaerobic exercise ,Methane - Abstract
Anaerobic digestion (AD) is increasingly being used and exploited as a strategy to generate biomethane, which can be used as a renewable and clean energy. AD rests on the biodegradation of organic compounds in anaerobic condition, and these organic compounds are generally agricultural-, industrial- and domestic-wastes. However, problems of AD decrease efficiency, as the result of bioreactor stress, are generally encountered. The primarily cause of this stress is the presence of high concentrations of inhibitory substances such as nitrate, sulfate, heavy metals and oxygen among others. Another cause of AD decrease efficiency is the use of organic compounds that are less amenable to biodegradation such as lignocellulosic compounds. One of the strategies to overcome these limitations is the addition in bioreactors of “stress resistant”- or “efficient biomethane generating”- microorganisms to improve AD process. This strategy, known as bioaugmentation, has been used for the last 15 years to increase biomethane production. In this review, work carried out on this bioaugmentation process has been summarised, and new strategies that could be used or exploited to improve the success of this approach have also been discussed.
- Published
- 2016
23. Update on the cometabolism of organic pollutants by bacteria
- Author
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Alexis Nzila
- Subjects
Pollutant ,Bacteria ,biology ,Health, Toxicology and Mutagenesis ,Microorganism ,Cometabolism ,General Medicine ,Substrate (biology) ,Biodegradation ,Toxicology ,biology.organism_classification ,Pollution ,Microbiology ,chemistry.chemical_compound ,Biodegradation, Environmental ,Bioremediation ,chemistry ,Environmental science ,Environmental Pollutants ,Biochemical engineering ,Organic Chemicals ,Environmental Pollution - Abstract
Each year, tons of various types of molecules pollute our environment, and their elimination is one of the major challenges human kind is facing. Among the strategies to eliminate these pollutants is their biodegradation by microorganisms. However, many pollutants cannot be used efficiently as growth substrates by microorganisms. Biodegradation of such molecules by cometabolism has been reported, which is the ability of a microorganism to biodegrade a pollutant without using it as a growth-substrate (non-growth-substrate), while sustaining its own growth by assimilating a different substrate (growth-substrate). This approach has been used in the field of bioremediation, however, its potential has not been fully exploited yet. This review summarises the work carried out on the cometabolism of important recalcitrant pollutants, and presents strategies that can be used to improve ways of identifying microorganisms that can cometabolise such recalcitrant pollutants.
- Published
- 2013
24. Biotransformation and biocatalysis: roles and applications in the discovery of antimalarials
- Author
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Alexis Nzila, Stefan Louw, Nyaradzo T. L. Chigorimbo-Murefu, Mathew Njoroge, Collen Masimirembwa, and Kelly Chibale
- Subjects
Pharmacology ,Plasmodium ,Drug discovery ,Metabolite ,Computational biology ,Biology ,Malaria ,Drug biotransformation ,Antimalarials ,chemistry.chemical_compound ,chemistry ,Biotransformation ,Biocatalysis ,Drug Discovery ,Animals ,Humans ,Molecular Medicine ,Active metabolite - Abstract
Several strategies to discover new antimalarials have been proposed to augment and complement the conventional drug-discovery paradigm. One approach, which has not yet been fully exploited, is the use of drug biotransformation to identify new active molecules. This concept rests on the use of the biotransformation of drugs to their pharmacologically active metabolites. This approach has been used successfully in human chemotherapy, with the discovery and development of several metabolite-based drugs. This review looks at the contribution that biotransformations can play in antimalarial drug discovery.
- Published
- 2012
25. Biological CO2 fixation using Chlorella vulgaris and its thermal characteristics through thermogravimetric analysis
- Author
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Mohammad M. Hossain, Alexis Nzila Mouanda, Saad Aldin M. Ali, and Shaikh A. Razzak
- Subjects
020209 energy ,Chlorella vulgaris ,Biomass ,Photobioreactor ,chemistry.chemical_element ,Bioengineering ,02 engineering and technology ,010501 environmental sciences ,01 natural sciences ,Models, Biological ,chemistry.chemical_compound ,Bioreactors ,Botany ,0202 electrical engineering, electronic engineering, information engineering ,Bioreactor ,0105 earth and related environmental sciences ,Carbon fixation ,General Medicine ,Carbon Dioxide ,Productivity (ecology) ,chemistry ,Environmental chemistry ,Carbon dioxide ,Carbon ,Biotechnology - Abstract
The present research is focused on cultivation of microalgae strain Chlorella vulgaris for bio-fixation of CO2 coupled with biomass production. In this regard, a single semi-batch vertical tubular photobioreactor and four similar photobioreactors in series have been employed. The concentration of CO2 in the feed stream was varied from 2 to 12 % (v/v) by adjusting CO2 to air ratio. The amount of CO2 capture and algae growth were monitored by measuring decrease of CO2 concentration in the gas phase, microalgal cell density, and algal biomass production rate. The results show that 4 % CO2 gives maximum amount of biomass (0.9 g L(-1)) and productivity (0.118 g L(-1) day(-1)) of C. vulgaris in a single reactor. In series reactors, average productivity per reactor found to be 0.078 g L(-1) day(-1). The maximum CO2 uptake for single reactor also found with 4 % CO2, and it is around 0.2 g L(-1) day(-1). In series reactors, average CO2 uptake is 0.13 g L(-1) day(-1) per reactor. TOC analysis shows that the carbon content of the produced biomass is around 40.67 % of total weight. The thermochemical characteristics of the cultivated C. vulgaris samples were analyzed in the presence of air. All samples burn above 200 °C and the combustion rate become faster at around 600 °C. Almost 98 wt% of the produced biomass is combustible in this range.
- Published
- 2016
26. Malaria in the Era of Food Fortification With Folic Acid
- Author
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John E. Hyde, Alexis Nzila, and John Okombo
- Subjects
0301 basic medicine ,Exacerbation ,Geography, Planning and Development ,Population ,Disease ,03 medical and health sciences ,0302 clinical medicine ,Folic Acid ,Environmental health ,parasitic diseases ,medicine ,Animals ,Humans ,030212 general & internal medicine ,education ,education.field_of_study ,Nutrition and Dietetics ,biology ,business.industry ,Incidence (epidemiology) ,Food fortification ,Plasmodium falciparum ,medicine.disease ,biology.organism_classification ,Biotechnology ,Malaria ,030104 developmental biology ,Folic acid ,Africa ,Dietary Supplements ,Food, Fortified ,business ,Food Science - Abstract
Food fortified with folic acid has been available for consumption in North America for over a decade. This strategy has led to an increase in folate levels in the general population and, more importantly, a significant decrease in the incidence of neural tube defects. However, this increase in folate intake has been associated with a greater risk of cancer disease. Many African countries are now embracing this concept; however, because folate promotes malaria parasite division, as it does in cancer cells, there is a possibility of malaria exacerbation if folate intake is increased. A precedent for such a concern is the now compelling evidence showing that an increase in iron intake can lead to a higher malaria risk; as a result, mass administration of iron in malaria-endemic areas is not recommended. In this article, we review work on the effect of folate on malaria parasites. Although this topic has received little research attention, the available data suggest that the increase in folate concentration could be associated with an increase in malaria infection. Thus, the introduction of food fortification with folic acid in malaria-endemic areas should be attended by precautionary programs to monitor the risk of malaria.
- Published
- 2016
27. Update on the in vivo tolerance and in vitro reduced susceptibility to the antimalarial lumefantrine
- Author
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Eric O Ohuma, John Okombo, Assad A. Al-Thukair, and Alexis Nzila
- Subjects
Microbiology (medical) ,Plasmodium ,Artemether/lumefantrine ,Genotype ,Drug Resistance ,Drug resistance ,Pharmacology ,Biology ,Lumefantrine ,Antimalarials ,chemistry.chemical_compound ,Parasitic Sensitivity Tests ,Drug tolerance ,Chloroquine ,parasitic diseases ,medicine ,Humans ,Pharmacology (medical) ,Artemether ,Artemisinin ,Asia, Southeastern ,Fluorenes ,Drug Tolerance ,medicine.disease ,Malaria ,Infectious Diseases ,chemistry ,Ethanolamines ,medicine.drug - Abstract
Coartem(®), the combination of artemether (an artemisinin derivative) and lumefantrine, has been adopted as the first-line treatment for uncomplicated malaria in many countries. The emergence of resistance to artemisinin derivatives has now been proven in South-East Asia, and there is concern that this may spread to other endemic areas. Strategies to contain and control the spread of artemisinin resistance have been proposed. On the other hand, not much attention has been given to lumefantrine. Indeed, for more than 7 years, reports have been emerging that the use of Coartem(®) is associated with rapid selection of lumefantrine-tolerant parasites. These parasites can survive in the presence of sub-therapeutic lumefantrine concentrations, and, interestingly, this in vivo phenotype is translated in vitro into reduced susceptibility to lumefantrine. As a result, such parasites could form the setting in which lumefantrine resistance would emerge. Thus, identifying genetic markers that reflect this phenotype (both in vitro and in vivo) could yield information on the mechanisms of lumefantrine resistance. More interestingly, lumefantrine tolerance is associated with an increase in chloroquine susceptibility, raising the possibility of re-introducing chloroquine. In this work, we have reviewed the current knowledge, and we present existing challenges and gaps with regard to the mechanisms of in vivo tolerance and in vitro reduced susceptibility to lumefantrine. The re-introduction of chloroquine in areas of high lumefantrine resistance is also discussed.
- Published
- 2012
28. Amodiaquine resistance in Plasmodium berghei is associated with PbCRT His95Pro mutation, loss of chloroquine, artemisinin and primaquine sensitivity, and high transcript levels of key transporters
- Author
-
Beatrice Irungu, Loise Ndung'u, Daniel Kiboi, Esther Magiri, Benard Langat, Joseph K. Ng’ang’a, and Alexis Nzila
- Subjects
0301 basic medicine ,biology ,business.industry ,030106 microbiology ,Medicine (miscellaneous) ,Plasmodium falciparum ,Amodiaquine ,biology.organism_classification ,Virology ,General Biochemistry, Genetics and Molecular Biology ,3. Good health ,Multiple drug resistance ,03 medical and health sciences ,030104 developmental biology ,Chloroquine ,Piperaquine ,parasitic diseases ,medicine ,Plasmodium berghei ,Artemether ,Artemisinin ,business ,medicine.drug - Abstract
Background: The human malaria parasite Plasmodium falciparum has evolved drug evasion mechanisms to all available antimalarials. The combination of amodiaquine-artesunate is among the drug of choice for treatment of uncomplicated malaria. In this combination, a short-acting, artesunate is partnered with long-acting, amodiaquine for which resistance may emerge rapidly especially in high transmission settings. Here, we used a rodent malaria parasite Plasmodium berghei ANKA as a surrogate of P. falciparum to investigate the mechanisms of amodiaquine resistance. Methods: We used the ramp up approach to select amodiaquine resistance. We then employed the 4-Day Suppressive Test to measure the resistance level and determine the cross-resistance profiles. Finally, we genotyped the resistant parasite by PCR amplification, sequencing and relative quantitation of mRNA transcript of targeted genes. Results: Submission of the parasite to amodiaquine pressure yielded resistant line within thirty-six passages. The effective doses that reduced 90% of parasitaemia (ED90) of the sensitive and resistant lines were 4.29mg/kg and 19.13mg/kg respectively. The selected parasite retained resistance after ten passage cycles in the absence of the drug and freezing at -80ºC for one month with ED90 of 20.34mg/kg and 18.22mg/kg. The parasite lost susceptibility to chloroquine by (6-fold), artemether (10-fold), primaquine (5-fold), piperaquine (2-fold) and lumefantrine (3-fold). Sequence analysis of Plasmodium berghei chloroquine-resistant transporter revealed His95Pro mutation. We found no variation in the nucleotide sequences of Plasmodium berghei multidrug resistance gene-1 (Pbmdr1), Plasmodium berghei deubiquitinating enzyme-1 or Plasmodium berghei Kelch13 domain. However, high mRNA transcripts of essential transporters; Pbmdr1, V-type/H+ pumping pyrophosphatase-2 and sodium hydrogen ion exchanger-1 and Ca2+/H+ antiporter accompanies amodiaquine resistance. Conclusions: The selection of amodiaquine resistance yielded stable “multidrug-resistant’’ parasites and thus may be used to study shared resistance mechanisms associated with other antimalarial drugs. Genome-wide analysis of the parasite may elucidate other functionally relevant genes controlling AQ resistance in P. berghei.
- Published
- 2018
29. Modulators of the efficacy and toxicity of drugs in malaria treatment
- Author
-
Roma Chilengi and Alexis Nzila
- Subjects
Pharmacology ,Drug ,medicine.medical_specialty ,business.industry ,media_common.quotation_subject ,Drug resistance ,Toxicology ,medicine.disease ,Drug Resistance, Multiple ,Intestinal absorption ,Malaria ,Disease course ,Antimalarials ,Pharmacotherapy ,Drug Discovery ,Toxicity ,medicine ,Humans ,Drug Therapy, Combination ,Antimalarial Agent ,Intensive care medicine ,business ,media_common - Abstract
The burgeoning problem of drug resistance in malaria requires the urgent discovery of new drugs. Discovery of an antimalarial agent that fulfills the requirements of a mass-treatment drug is challenging. Such an antimalarial drug should be safe for infants and children, be efficacious during a treatment course of 3-5 days, have good intestinal absorption, and be inexpensive. Such conditions are difficult to meet, which explains (at least in part) the paucity of antimalarial drugs. Development of antimalarial drugs has been based on two orthodox approaches: drugs are discovered from medicinal plants or synthetic chemistry. However, recent observation of human chemotherapy and pharmacopeia suggests that other strategies could be used to discover new drugs or to extend the therapeutic lifetime of failing drugs. In this review, we present evidence that the use of modulators of the efficacy and toxicity of drugs will lead to the discovery of new drugs and extend the therapeutic lifetime of existing agents.
- Published
- 2010
30. Preclinical Evaluation of the Antifolate QN254, 5-Chloro- N ′6′-(2,5-Dimethoxy-Benzyl)-Quinazoline-2,4,6-Triamine, as an Antimalarial Drug Candidate
- Author
-
Alexis Nzila, Sergio Wittlin, Bin Zou, Véronique Dartois, Matthias Rottmann, Supannee Taweechai, Cherdsak Maneeruttanarungroj, Josephine Wong, Reto Brun, Sumalee Kamchonwongpaisan, Yongyuth Yuthavong, Stevens M. Kiara, Penchit Chitnumsub, Ngai Ling Ma, Bryan K. S. Yeung, Thierry T. Diagana, Thomas H. Keller, Margaret Weaver, Suresh B. Lakshminarayana, and Anne Goh
- Subjects
Male ,Models, Molecular ,Plasmodium berghei ,Plasmodium falciparum ,Drug Resistance ,Administration, Oral ,Biological Availability ,Drug resistance ,In Vitro Techniques ,Pharmacology ,Antimalarials ,Mice ,chemistry.chemical_compound ,Therapeutic index ,Parasitic Sensitivity Tests ,parasitic diseases ,Dihydrofolate reductase ,medicine ,Quinazoline ,Animals ,Humans ,Pharmacology (medical) ,Malaria, Falciparum ,Rats, Wistar ,biology ,biology.organism_classification ,Malaria ,Rats ,Tetrahydrofolate Dehydrogenase ,Pyrimethamine ,Infectious Diseases ,chemistry ,Mutation ,Antifolate ,Quinazolines ,biology.protein ,Folic Acid Antagonists ,Female ,medicine.drug - Abstract
Drug resistance against dihydrofolate reductase (DHFR) inhibitors—such as pyrimethamine (PM)—has now spread to almost all regions where malaria is endemic, rendering antifolate-based malaria treatments highly ineffective. We have previously shown that the di-amino quinazoline QN254 [5-chloro- N ′6′-(2,5-dimethoxy-benzyl)-quinazoline-2,4,6-triamine] is active against the highly PM-resistant Plasmodium falciparum V1S strain, suggesting that QN254 could be used to treat malaria in regions with a high prevalence of antifolate resistance. Here, we further demonstrate that QN254 is highly active against Plasmodium falciparum clinical isolates, displaying various levels of antifolate drug resistance, and we provide biochemical and structural evidence that QN254 binds and inhibits the function of both the wild-type and the quadruple-mutant (V1S) forms of the DHFR enzyme. In addition, we have assessed QN254 oral bioavailability, efficacy, and safety in vivo . The compound displays favorable pharmacokinetic properties after oral administration in rodents. The drug was remarkably efficacious against Plasmodium berghei and could fully cure infected mice with three daily oral doses of 30 mg/kg. In the course of these efficacy studies, we have uncovered some dose limiting toxicity at higher doses that was confirmed in rats. Thus, despite its relative in vitro selectivity toward the Plasmodium DHFR enzyme, QN254 does not show the adequate therapeutic index to justify its further development as a single agent.
- Published
- 2010
31. In vitro selection of Plasmodium falciparum drug-resistant parasite lines
- Author
-
Alexis Nzila and Leah Mwai
- Subjects
Microbiology (medical) ,Mutation rate ,mutation rate ,Plasmodium falciparum ,030231 tropical medicine ,Drug Resistance ,Reviews ,Drug resistance ,Biology ,Antimalarials ,03 medical and health sciences ,clones ,resistance indexes ,0302 clinical medicine ,Antibiotic resistance ,medicine ,Animals ,Pharmacology (medical) ,Selection, Genetic ,Selection (genetic algorithm) ,030304 developmental biology ,Pharmacology ,Genetics ,0303 health sciences ,Mefloquine ,per-parasite resistant frequency ,biology.organism_classification ,medicine.disease ,3. Good health ,Infectious Diseases ,Parasitology ,‘accelerated resistance to multidrug’ ,Malaria ,medicine.drug - Abstract
The in vitro selection of antimicrobial resistance in important pathogens can provide critical information on the genetic basis of drug resistance, and such information can be used to predict, anticipate and even contain the spread of resistance in clinical practice. For instance, the discovery of the role of pfmdr1 in mefloquine resistance in malaria parasites resulted from in vitro studies. However, the in vitro selection of resistance is difficult, challenging and time consuming. In this review, we discuss the key parameters that impact on the efficiency of the in vitro selection of resistance, and propose strategies to improve and streamline this process.
- Published
- 2009
32. In Vitro Activities of Piperaquine, Lumefantrine, and Dihydroartemisinin in Kenyan Plasmodium falciparum Isolates and Polymorphisms in p fcrt and p fmdr1
- Author
-
Steffen Borrmann, Kevin Marsh, Anja Rippert, Peter C. Bull, Abdi Abdirahman, Alexis Nzila, Leah Mwai, Lewa Pole, Steven M. Kiara, and Abdi Diriye
- Subjects
Pharmacology ,Genetics ,biology ,medicine.medical_treatment ,Dihydroartemisinin ,Plasmodium falciparum ,medicine.disease ,biology.organism_classification ,Lumefantrine ,Molecular biology ,Apicomplexa ,chemistry.chemical_compound ,Infectious Diseases ,chemistry ,Chloroquine ,Piperaquine ,medicine ,Pharmacology (medical) ,Artemisinin ,Malaria ,medicine.drug - Abstract
We have analyzed the in vitro chemosensitivity profiles of 115 Kenyan isolates for chloroquine (CQ), piperaquine, lumefantrine (LM), and dihydroartemisinin in association with polymorphisms in pfcrt at codon 76 and pfmdr 1 at codon 86, as well as with variations of the copy number of pfmdr 1 . The median drug concentrations that inhibit 50% of parasite growth (IC 50 s) were 41 nM (interquartile range [IQR], 18 to 73 nM), 50 nM (IQR, 29 to 96 nM), 32 nM (IQR, 17 to 46 nM), and 2 nM (IQR, 1 to 3 nM) for CQ, LM, piperaquine, and dihydroartemisinin, respectively. The activity of CQ correlated inversely with that of LM ( r 2 = −0.26; P = 0.02). Interestingly, parasites for which LM IC 50 s were higher were wild type for pfcrt -76 and pfmdr 1 - 86 . All isolates had one pfmdr 1 copy. Thus, the decrease in LM activity is associated with the selection of wild-type pfcrt - 76 and pfmdr 1 - 86 parasites, a feature that accounts for the inverse relationship between CQ and LM. Therefore, the use of LM-artemether is likely to lead to the selection of more CQ-susceptible parasites.
- Published
- 2009
33. Methotrexate and aminopterin lack in vivo antimalarial activity against murine malaria species
- Author
-
Sergio Wittlin, Beatrice Irungu, G.M. Rukunga, Bernard Langat, Alexis Nzila, and Daniel Kiboi
- Subjects
Plasmodium ,Plasmodium berghei ,Plasmodium vinckei ,Immunology ,Administration, Oral ,Biological Availability ,Pharmacology ,Aminopterin ,Plasmodium chabaudi ,Mice ,chemistry.chemical_compound ,Folic Acid ,parasitic diseases ,medicine ,Animals ,Enzyme Inhibitors ,biology ,Plasmodium falciparum ,Plasmodium yoelii ,General Medicine ,biology.organism_classification ,Malaria ,Methotrexate ,Pyrimethamine ,Infectious Diseases ,chemistry ,Antifolate ,Folic Acid Antagonists ,Female ,Parasitology ,medicine.drug - Abstract
The antifolate anticancer drug methotrexate (MTX) has potent activity against Plasmodium falciparum in vitro. Experience of its use in the treatment of rheumatoid arthritis indicates that it could be safe and efficacious for treating malaria. We sought to establish a murine malaria model to study the mechanism of action and resistance of MTX and its analogue aminopterin (AMP). We used Plasmodium berghei, Plasmodium yoelii yoelii, Plasmodium chabaudi and Plasmodium vinckei. None of these species were susceptible to either drug. We have also tested the efficacy of pyrimethamine in combination with folic acid in P. berghei, and data indicate that folic acid does not influence pyrimethamine efficacy, which suggests that P. berghei may not transport folate. Since MTX and AMP utilise folate receptor/transport to gain access to cells, their lack of efficacy against the four tested murine malaria species may be the result of inefficiency of drug transport.
- Published
- 2009
34. In Vitro Chemosensitization of Plasmodium falciparum to Antimalarials by Verapamil and Probenecid
- Author
-
Alexis Nzila, Steven Muriithi, and Victor Masseno
- Subjects
Plasmodium falciparum ,Pharmacology ,urologic and male genital diseases ,Antimalarials ,Parasitic Sensitivity Tests ,Chemosensitization ,In vivo ,Chloroquine ,Piperaquine ,parasitic diseases ,polycyclic compounds ,medicine ,Animals ,Pharmacology (medical) ,Adjuvants, Pharmaceutic ,Quinine ,biology ,Probenecid ,Chemistry ,biology.organism_classification ,female genital diseases and pregnancy complications ,Infectious Diseases ,Verapamil ,Susceptibility ,medicine.drug - Abstract
We tested the effect of probenecid and verapamil in chemosensitizing Plasmodium falciparum to 14 antimalarials using the multidrug-resistant strain V1S and the drug-sensitive 3D7. Verapamil chemosensitizes V1S to quinine and chloroquine. Interestingly, probenecid profoundly chemosensitizes V1S to piperaquine. Thus, probenecid could be used to increase piperaquine efficacy in vivo.
- Published
- 2009
35. Effect of folate derivatives on the activity of antifolate drugs used against malaria and cancer
- Author
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Eunice Nduati, Sheila C. Ommeh, Alexis Nzila, Victor Masseno, Steven M. Kiara, Abdi Diriye, Leah Mwai, and Gilbert Kokwaro
- Subjects
Drug ,media_common.quotation_subject ,Plasmodium falciparum ,Leucovorin ,Antineoplastic Agents ,Biology ,Pharmacology ,Aminopterin ,Antimalarials ,Inhibitory Concentration 50 ,03 medical and health sciences ,chemistry.chemical_compound ,Folinic acid ,Folic Acid ,parasitic diseases ,medicine ,Animals ,Tetrahydrofolates ,030304 developmental biology ,media_common ,Original Paper ,0303 health sciences ,Molecular Structure ,General Veterinary ,Triazines ,030306 microbiology ,General Medicine ,biology.organism_classification ,3. Good health ,Methotrexate ,Pyrimethamine ,Infectious Diseases ,Trimetrexate ,Proguanil ,chemistry ,Insect Science ,Antifolate ,Folic Acid Antagonists ,Parasitology ,medicine.drug - Abstract
The folate derivatives folic acid (FA) and folinic acid (FNA) decrease the in vivo and in vitro activities of antifolate drugs in Plasmodium falciparum. However, the effects of 5-methyl-tetrahydrofolate (5-Me-THF) and tetrahydrofolate (THF), the two dominant circulating folate forms in humans, have not been explored yet. We have investigated the effects of FA, FNA, 5-Me-THF, and THF on the in vitro activity of the antimalarial antifolates pyrimethamine and chlorcycloguanil and the anticancer antifolates methotrexate (MTX), aminopterin, and trimetrexate (TMX), against P. falciparum. The results indicate that these anticancers are potent against P. falciparum, with IC50
- Published
- 2008
36. Artemether/lumefantrine in the treatment of uncomplicated falciparum malaria
- Author
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Leah Mwai, Gilbert Kokwaro, and Alexis Nzila
- Subjects
medicine.medical_specialty ,Artemether/lumefantrine ,Lumefantrine ,law.invention ,chemistry.chemical_compound ,law ,parasitic diseases ,medicine ,Humans ,Pharmacology (medical) ,Artemether ,Malaria, Falciparum ,Artemisinin ,Intensive care medicine ,Pharmacology ,Fluorenes ,Clinical pharmacology ,biology ,Mefloquine ,business.industry ,Plasmodium falciparum ,General Medicine ,medicine.disease ,biology.organism_classification ,Artemisinins ,Drug Combinations ,chemistry ,Ethanolamines ,business ,Malaria ,medicine.drug - Abstract
At present, artemether/lumefantrine (AL) is the only fixed-dose artemisinin-based combination therapy recommended and pre-qualified by WHO for the treatment of uncomplicated malaria caused by Plasmodium falciparum. It has been shown to be effective both in sub-Saharan Africa and in areas with multi-drug resistant P. falciparum in southeast Asia. It is currently recommended as first-line treatment for uncomplicated malaria in several countries. However, AL has a complex treatment regimen and the issues of adherence to treatment with AL by adult patients and real-life effectiveness in resource-poor settings will be critical in determining its useful therapeutic life, especially in Africa, where the major burden of malaria is felt. There are also issues of safety of the artemisinin derivatives, including AL, which will need to be monitored as their use in resource-poor settings becomes more widespread. There are limited pharmacokinetic studies of AL in African patients, and the relationship between plasma drug concentration and efficacy in these patients is unknown. Moreover, the effects of factors such as concurrently administered drugs, malnutrition and co-infections with HIV and helminths in malaria patients are not well understood. These will need to be addressed, although a few studies on possible drug-drug interactions with commonly used drugs, such as quinine, mefloquine and ketoconazole, have been reported. This review focuses on the status of clinical pharmacology, efficacy and real-life effectiveness of AL under a variety of settings, and highlights some of the challenges that face policy makers during the deployment of AL, especially in Africa, with regards to ensuring that those who most need this therapy will not be denied access due to official inefficiency in procurement and distribution processes.
- Published
- 2006
37. Antimalarial activity of isoquine against Kenyan Plasmodium falciparum clinical isolates and association with polymorphisms in pfcrt and pfmdr1 genes
- Author
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Abdi Abdirahman, Steve A. Ward, Eric O Ohuma, John Okombo, Leah Mwai, Steven M. Kiara, Alexis Nzila, and Steffen Borrmann
- Subjects
Microbiology (medical) ,medicine.medical_treatment ,Metabolite ,Plasmodium falciparum ,Protozoan Proteins ,Dihydroartemisinin ,Amodiaquine ,Biology ,Pharmacology ,Lumefantrine ,Antimalarials ,Inhibitory Concentration 50 ,chemistry.chemical_compound ,Parasitic Sensitivity Tests ,Chloroquine ,parasitic diseases ,medicine ,Humans ,Pharmacology (medical) ,Malaria, Falciparum ,IC50 ,Polymorphism, Genetic ,Membrane Transport Proteins ,medicine.disease ,biology.organism_classification ,Kenya ,Infectious Diseases ,chemistry ,Multidrug Resistance-Associated Proteins ,Malaria ,medicine.drug - Abstract
Background The use of amodiaquine in prophylaxis is associated with serious toxicity, resulting from its metabolic conversion into a reactive quinone-imine metabolite by the hepatic cytochrome P450. To circumvent this toxicity, several amodiaquine analogues that lack the potential to form a quinone-imine derivative, while retaining antimalarial activity, have been designed. Isoquine is one of these promising molecules that has already reached Phase I clinical trials in humans. Methods We analysed the in vitro activity of isoquine against 62 Plasmodium falciparum isolates collected in Kenya and the association of this activity with polymorphisms in pfcrt and pfmdr1 genes. Results The median concentration of isoquine that inhibited 50% of parasite growth (IC50) was 9 nM, compared with 56 nM chloroquine, 8 nM amodiaquine, 10 nM desethylamodiaquine, 69 nM lumefantrine and 1 nM dihydroartemisinin. Isoquine activity was correlated with polymorphisms in pfcrt at codon 76, but not in pfmdr1 at codon 86. Conclusions The high activity of isoquine against field isolates, including chloroquine-resistant isolates, with IC50
- Published
- 2012
38. Biodegradation of highly complex polyaromatic-hydrocarbon pyrene by Bacillus lenichiformis and Ralstonia sp from the coastal region of Saudi Arabia
- Author
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Assad Thukair, Saravanan Sankara, Mohammed Musa Musa, Alexis Nzila, and Basheer Chanbasha
- Subjects
0301 basic medicine ,Bacillus (shape) ,biology ,Chemistry ,Bioengineering ,General Medicine ,Biodegradation ,biology.organism_classification ,Ralstonia sp ,Microbiology ,03 medical and health sciences ,Polyaromatic hydrocarbon ,chemistry.chemical_compound ,030104 developmental biology ,Pyrene ,Molecular Biology ,Biotechnology - Published
- 2016
39. SHORT REPORT: ASSOCIATION BETWEEN CHLOROQUINE AND AMODIAQUINE RESISTANCE AND ALLELIC VARIATION IN THE PLASMODIUM FALCIPARUM MULTIPLE DRUG RESISTANCE 1 GENE AND THE CHLOROQUINE RESISTANCE TRANSPORTER GENE IN ISOLATES FROM THE UPPER NILE IN SOUTHERN SUDAN
- Author
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Kees Keus, Alexis Nzila, Ingrid van den Broek, and Edwin Ochong
- Subjects
Sulfadoxine ,medicine.medical_treatment ,Plasmodium falciparum ,Protozoan Proteins ,Amodiaquine ,Pharmacology ,Sudan ,Apicomplexa ,Antimalarials ,Parasitic Sensitivity Tests ,Chloroquine ,Virology ,parasitic diseases ,medicine ,Animals ,Humans ,Malaria, Falciparum ,Allele ,Alleles ,biology ,Genetic Variation ,Membrane Proteins ,Membrane Transport Proteins ,biology.organism_classification ,Drug Resistance, Multiple ,Multiple drug resistance ,Infectious Diseases ,Pyrimethamine ,ATP-Binding Cassette Transporters ,Parasitology ,medicine.drug - Abstract
Amodiaquine, a 4-aminoquinoline compound, is being considered as an alternative to chloroquine and pyrimethamine/sulfadoxine where resistance in Plasmodium falciparum to both drugs has been selected. Although amodiaquine is more potent than chloroquine, its effectiveness is reduced in areas where chloroquine resistance is high. We report an association of the P. falciparum chloroquine resistance transporter (pfcrt) gene and the P. falciparum multiple drug resistance 1 (pfmdr1) gene, two chloroquine resistance markers, with chloroquine and amodiaquine efficacy in vivo in southern Sudan. The data show that the allele of the pfcrt gene with a lysine to threonine change at codon 76 is strongly associated with both chloroquine and amodiaquine resistance. No such association was observed with the pfmdr1 gene.
- Published
- 2003
40. Chloroquine, sulfadoxine-pyrimethamine and amodiaquine efficacy for the treatment of uncomplicated Plasmodium falciparum malaria in Upper Nile, South Sudan
- Author
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Kees Keus, Ingrid van den Broek, Edwin Ochong, Alexis Nzila, B. Lowoko, and T. Gatkoi
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Sulfadoxine ,medicine.medical_treatment ,Drug Resistance ,DHPS ,Amodiaquine ,Pharmacology ,Sudan ,Antimalarials ,Chloroquine ,Internal medicine ,parasitic diseases ,medicine ,Humans ,Malaria, Falciparum ,Child ,Aged ,biology ,business.industry ,Public Health, Environmental and Occupational Health ,Plasmodium falciparum ,General Medicine ,Middle Aged ,medicine.disease ,biology.organism_classification ,Sulfadoxine/pyrimethamine ,Drug Combinations ,Pyrimethamine ,Treatment Outcome ,Infectious Diseases ,Child, Preschool ,Female ,Parasitology ,business ,Malaria ,medicine.drug - Abstract
The current first-line and second-line drugs for Plasmodium falciparum malaria in South Sudan, chloroquine and sulfadoxine-pyrimethamine (SP), were evaluated and compared with amodiaquine, in an MSF-Holland-run clinic in eastern Upper Nile, South Sudan from June to December 2001. Patients with uncomplicated malaria and fever were stratified by age group and randomly allocated to one of 3 treatment regimes. A total of 342 patients was admitted and followed for 14 d after treatment. The dropout rate was 10.2%. Of those who completed the study, 104 were treated with chloroquine (25 mg/kg, 3 d), 102 with SP (25 mg/kg sulfadoxine and 1.25 mg/kg pyrimethamine, single dose) and 101 with amodiaquine (25 mg/kg, 3 d). Adequate clinical response was observed in 88.5% of patients treated with chloroquine, 100% of patients treated with SP and 94.1% of patients treated with amodiaquine. In children aged5 years, the success rate was lower: 83.3% for chloroquine and 93.0% for amodiaquine. In adults no treatment failures were found, but children aged 5-15 years showed intermediate levels. In addition, we determined the initial genotypes of dhfr and dhps of 44 isolates from the SP-treated group and80% were found to be wild type for dhfr and 100% for dhps. Two percent of isolates had a single mutation and 16% had double mutations of dhfr. These data are in full agreement with the clinical effectiveness of SP. A change in malaria treatment protocols for South Sudan is recommended.
- Published
- 2003
41. Baseline In Vitro Activities of the Antimalarials Pyronaridine and Methylene Blue against Plasmodium falciparum Isolates from Kenya
- Author
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Lewa Pole, Eric O Ohuma, Alexis Nzila, Lynette Isabella Ochola, Steven M. Kiara, John Okombo, and Leah Mwai
- Subjects
Plasmodium falciparum ,Protozoan Proteins ,Biology ,Antimalarials ,chemistry.chemical_compound ,Parasitic Sensitivity Tests ,In vivo ,parasitic diseases ,Animals ,Humans ,Pharmacology (medical) ,Malaria, Falciparum ,Naphthyridines ,Gene ,Pharmacology ,Pyronaridine ,Polymorphism, Genetic ,biology.organism_classification ,Kenya ,Virology ,In vitro ,Methylene Blue ,Infectious Diseases ,chemistry ,Susceptibility ,Malaria falciparum ,Methylene blue - Abstract
We have analyzed the in vitro activities of pyronaridine and methylene blue against 59 Plasmodium falciparum isolates from Kenya in association with polymorphisms in Pfcrt (codon 76), Pfmdr1 (codon 86), and Pfnhe (full sequence). The median inhibitory concentrations that kill 50% of parasites were 13.5 and 3.3 nM for pyronaridine and methylene blue, respectively. Their activities were not associated with polymorphisms in these genes. The drugs' high in vitro activities indicate that they would be efficacious against Kenyan isolates in vivo .
- Published
- 2012
42. Genetic diversity of Plasmodium falciparum parasites from Kenya is not affected by antifolate drug selection
- Author
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Alexis Nzila, Carol Hopkins Sibley, Amanda Ross, E.K. Mberu, Eunice Nduati, and William M. Watkins
- Subjects
Fever ,Sulfadoxine ,medicine.medical_treatment ,Genes, Protozoan ,Plasmodium falciparum ,Drug Resistance ,Protozoan Proteins ,Antigens, Protozoan ,Drug resistance ,Dapsone ,Parasitemia ,Body Temperature ,Antimalarials ,Age Distribution ,Genotype ,medicine ,Animals ,Humans ,Alleles ,Merozoite Surface Protein 1 ,Genetics ,Genetic diversity ,Polymorphism, Genetic ,biology ,Genetic Variation ,Infant ,medicine.disease ,biology.organism_classification ,Kenya ,Virology ,Malaria ,Infectious Diseases ,Pyrimethamine ,Child, Preschool ,Folic Acid Antagonists ,Parasitology ,medicine.drug - Abstract
The genotypes of merozoite surface protein-1, merozoite surface protein-2 and glutamine rich protein are frequently used to distinguish recrudescence from reinfection when parasitaemia reappears after antimalarial drug treatment. However, none of the previous reports has clearly assessed the change of genetic diversity following drug treatment. In the present study, we have assessed the impact of pyrimethamine/sulfadoxine and chlorproguanil/dapsone on the genetic diversity of isolates and the multiplicity of infection in patient isolates from Kilifi, Kenya. We have analysed the length polymorphism of merozoite surface protein-1, merozoite surface protein-2 and glutamine rich protein and the data clearly show that treatment with pyrimethamine/sulfadoxine and chlorproguanil/dapsone did not change the multiplicity of infection found in patients, in contrast to the selection that these drugs exert on the genes encoded by the target enzymes. In addition, we report that children of less than 2 years tend to have fewer numbers of clones per isolate when compared with older children. Overall, this study shows that the selection for genes that confer drug resistance is not a factor in reducing the genetic diversity of parasite clones in a patient.
- Published
- 2002
43. Plasmodium falciparum: in vitro activity of sulfadoxine and dapsone in field isolates from Kenya: point mutations in dihydropteroate synthase may not be the only determinants in sulfa resistance
- Author
-
William M. Watkins, Carol Hopkins Sibley, Gilbert Kokwaro, Amanda Ross, Stephanie M. Monks, E.K. Mberu, Eunice Nduati, and Alexis Nzila
- Subjects
Genotype ,Sulfadoxine ,medicine.medical_treatment ,Plasmodium falciparum ,Immunology ,Drug Resistance ,DHPS ,Drug resistance ,Dapsone ,Antimalarials ,Parasitic Sensitivity Tests ,parasitic diseases ,medicine ,Animals ,Humans ,Point Mutation ,Malaria, Falciparum ,Child ,Alleles ,Antibacterial agent ,Dihydropteroate Synthase ,biology ,Infant ,General Medicine ,DNA, Protozoan ,biology.organism_classification ,Kenya ,Virology ,Tetrahydrofolate Dehydrogenase ,Infectious Diseases ,Child, Preschool ,Parasitology ,Dihydropteroate synthase ,medicine.drug - Abstract
We have determined the relationship between point mutations in the gene that encodes the sulfa target, dihydropteroate synthase (DHPS) and the chemosensitivity profile to sulfadoxine and dapsone in 67 isolates from Kilifi, Kenya. We assessed the presence of mutations at codons 436, 437, 540, 581, and 613 of dhps. The results showed that the dhps genotype had a strong influence on the sensitivity to sulfadoxine and dapsone, but that the correlation was far from perfect. Eleven isolates carried a wild-type dhps allele, but were resistant to sulfadoxine (IC(50) values10 microg/ml), and 4/28 isolates were classed as sensitive to sulfadoxine (IC(50) values10 microg/ml), but carried a triple mutant (436/437/613) allele of dhps. These data show that in low folate medium in vitro, the dhps genotype alone did not account completely for sulfadoxine or dapsone resistance; other factors such as the utilisation of exogenous folate must also be considered.
- Published
- 2002
44. Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine
- Author
-
Nahla B Gadalla, Badria B. El-Sayed, Mary C. Oguike, Mehul Dhorda, Ahmed Zeynudin, Sally Hamour, Jean-René Kiechel, A. Fabrice Some, Colin J. Sutherland, Erasmus Kamugisha, Philippe J Guerin, Didier Menard, Anders Björkman, Bernhards Ogutu, Alexis Nzila, Johan Ursing, Ric N. Price, Julie Thwing, Abdoulaye Djimde, Kasia Stepniewska, Francesco Checchi, Issaka Zongo, Nicole Berens-Riha, Frederick N. Baliraine, George O. Ademowo, Grant Dorsey, Fred Kironde, Gabrielle Fröberg, Catherine O. Falade, Lars Rombo, Christian Nsanzabana, Prabin Dahal, Teferi Eshetu, Samuel L. Nsobya, Simon Kariuki, Meghna Desai, Jacob D. Johnson, Frederick Eyase, Jean-Bosco Ouédraogo, Meera Venkatesan, Ishag Adam, Christopher V. Plowe, Cesar Arze, Birgit Schramm, Steffen Borrmann, Timothy M. E. Davis, Poul-Erik Kofoed, Billy Ngasala, Jean-François Faucher, Sandrine Houzé, Andreas Mårtensson, Philip J. Rosenthal, François Nosten, Maja Malmberg, Carol Hopkins Sibley, Patrice Piola, Anastasia Grivoyannis, Sabina Dahlström Otienoburu, Rina P. M. Wong, Clarissa Moriera, Leah Mwai, Jacques Lebras, Centre for Tropical Medicine and Global Health, University of Oxford, WorldWide Antimalarial Resistance Network (WWARN), University of Oxford [Oxford]-Churchill Hospital Oxford Centre for Haematology, Global Health Division, Menzies School of Health Research, Department of Microbiology, Tumour and Cell biology [Stockholm, Sweden] (Malaria Research), Karolinska Institutet [Stockholm], University of California [San Francisco] (UCSF), University of California, London School of Hygiene and Tropical Medicine (LSHTM), LECEMO - Les Cultures de l'Europe Méditérranéenne Occidentale - EA 3979 (LECEMO), Université Sorbonne Nouvelle - Paris 3, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), University of Maryland School of Medicine, University of Maryland System, German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), Department of Infectious and Tropical Diseases, University of Oxford [Oxford], Département d'épidémiologie des affections parasitaires (DEAP), Université de Bamako-Malaria Research and Training Center (MRTC)-Facultés de Médecine, de Pharmacie et d'Odonto-Stomatologie-Centre National de la Recherche Scientifique (CNRS), Neuroépidémiologie Tropicale (NET), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Drugs for Neglected Diseases Initiative, Kenya Medical Research Institute (KEMRI), Muhimbili University of Health and Allied Sciences, Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), Mahidol Oxford Tropical Medicine Research Unit (MORU), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], Makerere University [Kampala, Ouganda] (MAK), King Fahd University of Petroleum and Minerals (KFUPM), Institut de Recherche en Sciences de la Santé Bobo Dioulasso (INSSA), Université Polytechnique Nazi Boni Bobo-Dioulasso (UNB), Université de Washington Seattle, Epicentre [Paris] [Médecins Sans Frontières], The WorldWide Antimalarial Resistance Network is supported by the Bill and Melinda Gates Foundation., and The ASAQ Molecular Marker Study Group
- Subjects
Artemether/lumefantrine ,MESH: Lumefantrine ,Drug Resistance ,Protozoan Proteins ,Datasets as Topic ,Drug resistance ,Kaplan-Meier Estimate ,MESH: Genetic Markers ,Pharmacology ,MESH: Membrane Transport Proteins ,MESH: Genotype ,chemistry.chemical_compound ,0302 clinical medicine ,MESH: Risk Factors ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Risk Factors ,MESH: Child ,MESH: Datasets as Topic ,Artemether ,Artemisinin ,Malaria, Falciparum ,Child ,MESH: Protozoan Proteins ,MESH: Plasmodium falciparum ,0303 health sciences ,MESH: Artemether ,biology ,MESH: Malaria, Falciparum ,Artesunate/amodiaquine ,Chloroquine ,Articles ,MESH: Chloroquine ,MESH: Amino Acid Substitution ,MESH: Infant ,Artemisinins ,3. Good health ,Drug Combinations ,Infectious Diseases ,Ethanolamines ,Child, Preschool ,MESH: Drug Resistance ,Drug Therapy, Combination ,Multidrug Resistance-Associated Proteins ,Erratum ,MESH: Multidrug Resistance-Associated Proteins ,medicine.drug ,Genetic Markers ,Genotype ,030231 tropical medicine ,Plasmodium falciparum ,Amodiaquine ,Lumefantrine ,MESH: Ethanolamines ,03 medical and health sciences ,Antimalarials ,Virology ,MESH: Polymorphism, Genetic ,MESH: Artemisinins ,parasitic diseases ,medicine ,MESH: Fluorenes ,Humans ,[SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology ,MESH: Amodiaquine ,MESH: Kaplan-Meier Estimate ,MESH: Drug Combinations ,Fluorenes ,MESH: Humans ,Polymorphism, Genetic ,030306 microbiology ,MESH: Child, Preschool ,Infant ,Membrane Transport Proteins ,biology.organism_classification ,MESH: Antimalarials ,MESH: Drug Therapy, Combination ,chemistry ,Amino Acid Substitution ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Parasitology - Abstract
Erratum in :- Errata. [Am J Trop Med Hyg. 2015]- Erratum. [Am J Trop Med Hyg. 2019]; International audience; Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001 : were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.
- Published
- 2014
45. Chlorproguanil-dapsone for treatment of drug-resistant falciparum malaria in Tanzania
- Author
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Elizabeth Hills, Theonest K. Mutabingwa, E.K. Mberu, Peter Winstanley, William M. Watkins, Eunice Nduati, and Alexis Nzila
- Subjects
Adult ,medicine.medical_specialty ,Adolescent ,Genotype ,Sulfadoxine ,medicine.medical_treatment ,Plasmodium falciparum ,Drug Resistance ,DHPS ,Drug resistance ,Tanzania ,Antimalarials ,chemistry.chemical_compound ,Chloroquine ,Internal medicine ,parasitic diseases ,medicine ,Animals ,Humans ,Point Mutation ,Malaria, Falciparum ,Child ,biology ,General Medicine ,Middle Aged ,biology.organism_classification ,medicine.disease ,Drug Combinations ,Pyrimethamine ,Proguanil ,chemistry ,Child, Preschool ,Immunology ,Dapsone ,Malaria ,Chlorproguanil/dapsone ,medicine.drug - Abstract
Summary Background Resistance to the affordable malaria treatments chloroquine and pyrimethamine-sulfadoxine is seriously impeding malaria control through treatment in east Africa. We did an open, alternate drug allocation study to assess the efficacy of chlorproguanil-dapsone in the treatment of falciparum malaria clinically resistant to pyrimethamine-sulfadoxine. Methods Children younger than 5 years with non-severe falciparum malaria, attending Muheza district hospital in Tanzania, were treated with the standard regimen of pyrimethamine-sulfadoxine. Patients whose clinical symptoms resolved but who remained parasitaemic 7 days after pyrimethamine-sulfadoxine were followed up for 1 month. Clinical malaria episodes were retreated with either single dose pyrimethamine-sulfadoxine or a 3-day regimen of chlorproguanil-dapsone. Those with parasitaemia after 7 days were treated with chlorproguanil-dapsone. Parasite DNA was collected on day 7 after first treatment with pyrimethamine-sulfadoxine and we looked for point mutations in the genes encoding dihydrofolate reductase ( dhfr ) and dyhydropteroate synthetase ( dhps ). Findings 360 children were enrolled and treated with pyrimethamine-sulfadoxine. On day 7, 192 (55%) of 348 had cleared parasitaemia. Of the remaining 156 parasitaemic children, 140 (90%) were followed up to day 28, and 92 (66%) of 140 developed clinical malaria. These 92 patients were alternately retreated with either pyrimethamine-sulfadoxine (46) or chlorproguanil-dapsone (46). 28 (61%) of 46 children retreated with pyrimethamine-sulfadoxine were still parasitaemic at day 7, compared with three (15%) of 46 children retreated with chlorproguanil-dapsone. Resistance to pyrimethamine-sulfadoxine increased from 45% (156/348) at the first treatment to 61% (28/46) after retreatment. 83 of 85 parasite isolates collected after the first pyrimethamine-sulfadoxine treatment, and before and after the second treatments with pyrimethamine-sulfadoxine and chlorproguanil-dapsone showed triple-mutant dhfr alleles, associated with a variety of dhps mutations. Interpretation Most patients treated with pyrimethamine-sulfadoxine, who remain parasitaemic at day 7, develop new malaria symptoms within 1 month. Chlorproguanil-dapsone was a practicable therapy under these circumstances. Analysis of parasite dhfr and dhps before and after treatment supports the view that pyrimethamine-sulfadoxine resistance in this part of Africa is primarily due to parasites with three mutations in the dhfr domain.
- Published
- 2001
46. PlasmoView: a web-based resource to visualise global Plasmodium falciparum genomic variation
- Author
-
Mark D, Preston, Samuel A, Assefa, Harold, Ocholla, Colin J, Sutherland, Steffen, Borrmann, Alexis, Nzila, Pascal, Michon, Tran Tinh, Hien, Teun, Bousema, Christopher J, Drakeley, Issaka, Zongo, Jean-Bosco, Ouédraogo, Abdoulaye A, Djimde, Ogobara K, Doumbo, Francois, Nosten, Rick M, Fairhurst, David J, Conway, Cally, Roper, and Taane G, Clark
- Subjects
Internet ,drug resistance ,vaccine targets ,Base Sequence ,Plasmodium falciparum ,malaria ,Molecular Sequence Annotation ,DNA, Protozoan ,Polymorphism, Single Nucleotide ,Major Articles and Brief Reports ,parasitic diseases ,genomics ,Animals ,Humans ,Parasites ,Malaria, Falciparum ,Genome, Protozoan ,visualization - Abstract
Malaria is a global public health challenge, with drug resistance a major barrier to disease control and elimination. To meet the urgent need for better treatments and vaccines, a deeper knowledge of Plasmodium biology and malaria epidemiology is required. An improved understanding of the genomic variation of malaria parasites, especially the most virulent Plasmodium falciparum (Pf) species, has the potential to yield new insights in these areas. High-throughput sequencing and genotyping is generating large amounts of genomic data across multiple parasite populations. The resulting ability to identify informative variants, particularly single-nucleotide polymorphisms (SNPs), will lead to the discovery of intra- and inter-population differences and thus enable the development of genetic barcodes for diagnostic assays and clinical studies. Knowledge of genetic variability underlying drug resistance and other differential phenotypes will also facilitate the identification of novel mutations and contribute to surveillance and stratified medicine applications. The PlasmoView interactive web-browsing tool enables the research community to visualise genomic variation and annotation (eg, biological function) in a geographic setting. The first release contains over 600 000 high-quality SNPs in 631 Pf isolates from laboratory strains and four malaria-endemic regions (West Africa, East Africa, Southeast Asia and Oceania).
- Published
- 2013
47. Impact of folate supplementation on the efficacy of sulfadoxine/pyrimethamine in preventing malaria in pregnancy: the potential of 5-methyl-tetrahydrofolate
- Author
-
John Okombo, Alexis Nzila, and Anne M. Molloy
- Subjects
Microbiology (medical) ,Sulfadoxine ,medicine.medical_treatment ,Physiology ,Context (language use) ,chemistry.chemical_compound ,Antimalarials ,Folic Acid ,Pregnancy ,parasitic diseases ,Medicine ,Animals ,Humans ,Pharmacology (medical) ,Pregnancy Complications, Infectious ,Tetrahydrofolates ,Pharmacology ,Anencephaly ,biology ,business.industry ,Plasmodium falciparum ,biology.organism_classification ,medicine.disease ,Sulfadoxine/pyrimethamine ,Malaria ,Drug Combinations ,Infectious Diseases ,Pyrimethamine ,Treatment Outcome ,chemistry ,Antifolate ,Drug Therapy, Combination ,Female ,business ,medicine.drug - Abstract
Malaria remains the leading cause of mortality and morbidity in children under the age of 5 years and pregnant women. To counterbalance the malaria burden in pregnancy, an intermittent preventive treatment strategy has been developed. This is based on the use of the antifolate sulfadoxine/pyrimethamine, taken at specified intervals during pregnancy, and reports show that this approach reduces the malaria burden in pregnancy. Pregnancy is also associated with the risk of neural tube defects (NTDs), especially in women with low folate status, and folic acid supplementation is recommended in pregnancy to lower the risk of NTDs. Thus, in malaria-endemic areas, pregnant women have to take both antifolate medication to prevent malaria and folic acid to lower the risk of NTDs. However, the concomitant use of folate and antifolate is associated with a decrease in antifolate efficacy, exposing pregnant women to malaria. Thus, there is genuine concern that this strategy may not be appropriate. We have reviewed work carried out on malaria folate metabolism and antifolate efficacy in the context of folate supplementation. This review shows that: (i) the folate supplementation effect on antifolate efficacy is dose-dependent, and folic acid doses required to protect pregnant women from NTDs will not decrease antifolate activity; and (ii) 5-methyl-tetrahydrofolate, the predominant form of folate in the blood circulation, could be administered (even at high dose) concomitantly with antifolate without affecting antifolate efficacy. Thus, strategies exist to protect pregnant women from malaria while maintaining adequate folate levels in the body to reduce the occurrence of NTDs.
- Published
- 2013
48. Molecular Evidence of Greater Selective Pressure for Drug Resistance Exerted by the Long‐Acting Antifolate Pyrimethamine/Sulfadoxine Compared with the Shorter‐Acting Chlorproguanil/Dapsone on KenyanPlasmodium falciparum
- Author
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William M. Watkins, E.K. Mberu, Carol Hopkins Sibley, Alexis Nzila, Peter Winstanley, Stephanie A. Monks, and Eunice Nduati
- Subjects
Sulfadoxine ,medicine.medical_treatment ,Plasmodium falciparum ,Drug Resistance ,Dapsone ,Biology ,Pharmacology ,Antimalarials ,chemistry.chemical_compound ,parasitic diseases ,medicine ,Animals ,Immunology and Allergy ,Peptide Synthases ,Pyrimethamine-Sulfadoxine ,biology.organism_classification ,Virology ,Sulfadoxine/pyrimethamine ,Drug Combinations ,Tetrahydrofolate Dehydrogenase ,Pyrimethamine ,Infectious Diseases ,Proguanil ,chemistry ,Folic Acid Antagonists ,Dihydropteroate synthase ,Chlorproguanil/dapsone ,medicine.drug - Abstract
Pyrimethamine (PM) plus sulfadoxine (SD) is the last remaining affordable drug for treating uncomplicated malaria in Africa. The selective pressure exerted by the slowly eliminated combination PM/SD was compared with that exerted by the more rapidly eliminated combination chlorproguanil/dapsone (CPG/Dap) on Kenyan Plasmodium falciparum. Point mutations were analyzed in dihydrofolate reductase and dihydropteroate synthase and in the genetic diversity of 3 genes in isolates collected before and after CPG/Dap and PM/SD treatments. PM/SD was associated strongly with the disappearance of fully drug-sensitive parasites and with a significant increase in the prevalence of resistant parasites in subsequent parasitemias. However, this was not a characteristic of treatment with CPG/Dap. Moreover, most of the patients who returned with recrudescent infections were in the PM/SD-treated group. The data predict a longer useful therapeutic life for CPG/Dap than for PM/SD, and, thus, CPG/Dap is a preferable alternative for treatment of chloroquine-resistant falciparum malaria in sub-Saharan Africa.
- Published
- 2000
49. Towards an Understanding of the Mechanism of Pyrimethamine-Sulfadoxine Resistance in Plasmodium falciparum : Genotyping of Dihydrofolate Reductase and Dihydropteroate Synthase of Kenyan Parasites
- Author
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Carol Hopkins Sibley, H. Dayo, Peter Winstanley, E. K. Mberu, J. Sulo, Alexis Nzila, and William M. Watkins
- Subjects
Male ,Genotype ,Sulfadoxine ,medicine.medical_treatment ,Plasmodium falciparum ,Mutant ,Drug Resistance ,DHPS ,Antimalarials ,Mechanisms of Resistance ,parasitic diseases ,Dihydrofolate reductase ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Malaria, Falciparum ,Alleles ,Pharmacology ,Dihydropteroate Synthase ,biology ,Pyrimethamine-Sulfadoxine ,Infant ,biology.organism_classification ,Kenya ,Virology ,Tetrahydrofolate Dehydrogenase ,Pyrimethamine ,Infectious Diseases ,Child, Preschool ,biology.protein ,Female ,Dihydropteroate synthase ,medicine.drug - Abstract
The antifolate combination of pyrimethamine (PM) and sulfadoxine (SD) is the last affordable drug combination available for wide-scale treatment of falciparum malaria in Africa. Wherever this combination has been used, drug-resistant parasites have been selected rapidly. A study of PM-SD effectiveness carried out between 1997 and 1999 at Kilifi on the Kenyan coast has shown the emergence of RI and RII resistance to PM-SD (residual parasitemia 7 days after treatment) in 39 out of 240 (16.25%) patients. To understand the mechanism that underlies resistance to PM-SD, we have analyzed the dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genotypes of 81 patients. Fifty-one samples were obtained, before treatment, from patients who remained parasite free for at least 7 days after treatment. For a further 20 patients, samples were obtained before treatment and again when they returned to the clinic with parasites 7 days after PM-SD treatment. Ten additional isolates were obtained from patients who were parasitemic 7 days after treatment but who were not sampled before treatment. More than 65% of the isolates (30 of 46) in the initial group had wild-type or double mutant DHFR alleles, and all but 7 of the 47 (85%) had wild-type DHPS alleles. In the paired (before and after treatment) samples, the predominant combinations of DHFR and DHPS alleles before treatment were of triple mutant DHFR and double mutant DHPS (41% [7 of 17]) and of double mutant DHFR and double mutant DHPS (29% [5 of 17]). All except one of the posttreatment isolates had triple mutations in DHFR, and most of these were “pure” triple mutants. In these isolates, the combination of a triple mutant DHFR and wild-type DHPS was detected in 6 of 29 cases (20.7%), the combination of a triple mutant DHFR and a single mutant (A437G) DHPS was detected in 4 of 29 cases (13.8%), and the combination of a triple mutant DHFR and a double mutant (A437G, L540E) DHPS was detected in 16 of 29 cases (55.2%). These results demonstrate that the triply mutated allele of DHFR with or without mutant DHPS alleles is associated with RI and RII resistance to PM-SD. The prevalence of the triple mutant DHFR-double mutant DHPS combination may be an operationally useful marker for predicting the effectiveness of PM-SD as a new malaria treatment.
- Published
- 2000
50. Drugs for the treatment of malaria in the Kingdom of Saudi Arabia
- Author
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Alexis, Nzila and Ibrahim, Al-Zahrani
- Subjects
Antimalarials ,Plasmodium ,Species Specificity ,Animals ,Humans ,Malaria - Abstract
Current malaria treatments are based on the use of artemisinin based combinations. In the Kingdom of Saudi Arabia, the combination of pyrimethamine/sulfadoxine/artesunate is the first line of treatment of uncomplicated malaria, while lumefantrine/artemether (Coartem) is used as a second option. The treatment of severe malaria rests on the use of quinine or artesunate. In Saudi Arabia, most cases of malaria are imported, mainly from emigrant workers from the Indian subcontinent and the Eastern part of Africa. As a result, most parasites might have been exposed to antimalarials prior to coming to the country. Thus, knowledge of the pattern of resistance to these drugs outside the country could contribute to better management of the disease. In this review, we have summarized our current knowledge on the efficacy and resistance patterns of currently used antimalarials. Alternative treatments that could be used against malaria in the Kingdom are also discussed.
- Published
- 2013
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