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1. Comparative transcriptomics reveals the mechanism of antibacterial activity of fruit-derived dihydrochalcone flavonoids against Porphyromonas gingivalis .

Author

Wu D, Hao L, Liu X, Li X, and Zhao G

Subjects
Transcriptome, Gene Expression Profiling, Plant Extracts pharmacology, Plant Extracts chemistry, Porphyromonas gingivalis drug effects, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents chemistry, Chalcones pharmacology, Fruit chemistry, Microbial Sensitivity Tests, Flavonoids pharmacology
Abstract

Porphyromonas gingivalis causes various health issues through oral infections. This study investigates the antibacterial activities of food-derived dihydrochalcone flavonoids against Porphyromonas gingivalis and their mechanisms of antibacterial action through comparative transcriptome profiling. Susceptibility tests showed that two typical dihydrochalcone flavonoids (phloretin and phlorizin) had much lower minimum inhibitory concentrations (12.5 μg mL -1 and 50 μg mL -1 , respectively) than the common flavanone naringenin (100 μg mL -1 ). SEM observations and the LDH activity assay indicated obvious anomalies in cell morphology and increased cell membrane permeability, indicating the destructive effect of those compounds on the cell structure. These compounds might also induce apoptosis in P. gingivalis , as shown by the CLSM fluorescence images. Transcriptomic analysis revealed that the flavonoid treatment impacted DNA function and oxidative damage. These flavonoids may activate antioxidant-related pathways that are lethal to anaerobic bacteria like P. gingivalis . Additionally, the compounds resulted in the silencing of transposition-related genes, potentially inhibiting resistance-gene acquisition and expression. Phloretin regulated fatty acid metabolism pathways, which are related to the construction and maintenance of the cell membrane. This suggests a relationship between the structure and antibacterial activities of the tested compounds that share a flavonoid skeleton but differ in the C-ring and glucose moiety. This is the first report of the antibacterial activities and mechanisms of action of food-derived dihydrochalcone flavonoids at the transcriptome level, offering a promising approach for the development of new antibacterial agents from natural products and enhancing their applicability in treating diseases associated with oral pathogens as a substitute for antibiotics.

Published
2024
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2. Synthesis, Characterization, and Antimicrobial Efficacy of Photomicrobicidal Cellulose Paper.

Author

Carpenter BL, Scholle F, Sadeghifar H, Francis AJ, Boltersdorf J, Weare WW, Argyropoulos DS, Maggard PA, and Ghiladi RA

Subjects
Anti-Infective Agents administration & dosage, Anti-Infective Agents chemical synthesis, Cellulose administration & dosage, Cellulose chemical synthesis, Enterococcus faecium drug effects, Humans, Klebsiella pneumoniae drug effects, Light, Paper, Photosensitizing Agents chemical synthesis, Porphyrins administration & dosage, Porphyrins chemical synthesis, Porphyrins chemistry, Pseudomonas aeruginosa drug effects, Staphylococcus aureus drug effects, Anti-Infective Agents chemistry, Cellulose chemistry, Microbial Sensitivity Tests, Photosensitizing Agents chemistry
Abstract

Toward our goal of scalable, antimicrobial materials based on photodynamic inactivation, paper sheets comprised of photosensitizer-conjugated cellulose fibers were prepared using porphyrin and BODIPY photosensitizers, and characterized by spectroscopic (infrared, UV-vis diffuse reflectance, inductively coupled plasma optical emission) and physical (gel permeation chromatography, elemental, and thermal gravimetric analyses) methods. Antibacterial efficacy was evaluated against Staphylococcus aureus (ATCC-2913), vancomycin-resistant Enterococcus faecium (ATCC-2320), Acinetobacter baumannii (ATCC-19606), Pseudomonas aeruginosa (ATCC-9027), and Klebsiella pneumoniae (ATCC-2146). Our best results were achieved with a cationic porphyrin-paper conjugate, Por((+))-paper, with inactivation upon illumination (30 min, 65 ± 5 mW/cm(2), 400-700 nm) of all bacterial strains studied by 99.99+% (4 log units), regardless of taxonomic classification. Por((+))-paper also inactivated dengue-1 virus (>99.995%), influenza A (∼ 99.5%), and human adenovirus-5 (∼ 99%). These results demonstrate the potential of cellulose materials to serve as scalable scaffolds for anti-infective or self-sterilizing materials against both bacteria and viruses when employing a photodynamic inactivation mode of action.

Published
2015
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3. MDR M. tuberculosis outbreak clone in Eswatini missed by Xpert has elevated bedaquiline resistance dated to the pre-treatment era

Author

Elisabeth Sanchez-Padilla, Nazir Ahmed Ismail, Thomas Kohl, Christian Utpatel, Patrick Beckert, Stefan Niemann, Claudio U. Köser, Harald Hoffmann, Sönke Andres, Robin M. Warren, Bouke C. de Jong, Marisa Klopper, Matthias Merker, Florian P. Maurer, Shaheed V. Omar, Katharina Kranzer, Maryline Bonnet, Bernhard Kerschberger, Viola Dreyer, Ivan Barilar, Elisa Ardizzoni, Birgit Schramm, Gugu Maphalala, Forschungszentrum Borstel - Research Center Borstel, German Center for Infection Research (DZIF), Heidelberg University, Epicentre [Paris] [Médecins Sans Frontières], University of Cambridge [UK] (CAM), National Institute for Communicable Diseases [Johannesburg] (NICD), University of Pretoria [South Africa], University of the Witwatersrand [Johannesburg] (WITS), Stellenbosch University, Institute of Tropical Medicine [Antwerp] (ITM), London School of Hygiene and Tropical Medicine (LSHTM), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Université Montpellier 1 (UM1)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM), Infectious and Tropical Diseases Department [Montpellier], Institut de Recherche pour le Développement (IRD)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Namibia (UNAM), Parts of this work have been supported by the European Union TB-PAN-NET (FP7-223681) project, by Médecins Sans Frontières-Switzerland, and by German Center for Infection Research, Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germanys Excellence Strategy – EXC 2167, and Leibniz Science Campus Evolutionary Medicine of the LUNG (EvoLUNG). The funders had no role in the study design, in the collection, analysis, and interpretation of the data, in the writing of the report, and in the decision to submit the paper for publication., European Project: 223681,EC:FP7:HEALTH,FP7-HEALTH-2007-B,TB PAN-NET(2009), Niemann, Stefan [0000-0002-6604-0684], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, MESH: Mycobacterium tuberculosis, Antitubercular Agents, Drug resistance, Multidrug resistance, Disease Outbreaks, Clofazimine, chemistry.chemical_compound, Tuberculosis, Multidrug-Resistant, MESH: Disease Outbreaks, Diarylquinolines, MESH: Bacterial Proteins, Genetics (clinical), MESH: Microbial Sensitivity Tests, Resistance mutation, MESH: Diarylquinolines, Mycobacterium tuberculosis complex, Molecular Medicine, medicine.drug, MESH: Mutation, Tuberculosis, 030106 microbiology, Microbial Sensitivity Tests, Biology, 03 medical and health sciences, Bacterial Proteins, MESH: Eswatini, Genetics, medicine, Humans, Molecular Biology, MESH: Tuberculosis, Multidrug-Resistant, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Diagnostice escape, Research, MESH: Clone Cells, Resistance evolution, Treatment escape, Mycobacterium tuberculosis, rpoB, medicine.disease, biology.organism_classification, MESH: Antitubercular Agents, Virology, Clone Cells, Multiple drug resistance, MDR outbreak strains, 030104 developmental biology, chemistry, Treatment failure, Mutation, Bedaquiline, Eswatini
Abstract

Background Multidrug-resistant (MDR) Mycobacterium tuberculosis complex strains not detected by commercial molecular drug susceptibility testing (mDST) assays due to the RpoB I491F resistance mutation are threatening the control of MDR tuberculosis (MDR-TB) in Eswatini. Methods We investigate the evolution and spread of MDR strains in Eswatini with a focus on bedaquiline (BDQ) and clofazimine (CFZ) resistance using whole-genome sequencing in two collections ((1) national drug resistance survey, 2009–2010; (2) MDR strains from the Nhlangano region, 2014–2017). Results MDR strains in collection 1 had a high cluster rate (95%, 117/123 MDR strains) with 55% grouped into the two largest clusters (gCL3, n = 28; gCL10, n = 40). All gCL10 isolates, which likely emerged around 1993 (95% highest posterior density 1987–1998), carried the mutation RpoB I491F that is missed by commercial mDST assays. In addition, 21 (53%) gCL10 isolates shared a Rv0678 M146T mutation that correlated with elevated minimum inhibitory concentrations (MICs) to BDQ and CFZ compared to wild type isolates. gCL10 isolates with the Rv0678 M146T mutation were also detected in collection 2. Conclusion The high clustering rate suggests that transmission has been driving the MDR-TB epidemic in Eswatini for three decades. The presence of MDR strains in Eswatini that are not detected by commercial mDST assays and have elevated MICs to BDQ and CFZ potentially jeopardizes the successful implementation of new MDR-TB treatment guidelines. Measures to limit the spread of these outbreak isolates need to be implemented urgently.

Published
2020

4. Description of compensatory gyrA mutations restoring fluoroquinolone susceptibility in Mycobacterium tuberculosis

Author

Stéphanie Petrella, Alexandra Aubry, Nicolas Veziris, Hélène Ferrand, Claudine Mayer, Aurélie Bouige, Alix Pantel, Stéphanie Matrat, Wladimir Sougakoff, Université Pierre et Marie Curie - Paris 6 (UPMC), Microbiologie structurale - Structural Microbiology (Microb. Struc. (UMR_3528 / U-Pasteur_5)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Parts of this paper were presented at the ‘International Conference on Antimicrobial Agents and Chemotherapy’, USA, 2011 (C1-626), and at the EMBO Conference ‘Tuberculosis 2012’, France, 2012 (TUBERCULOSIS2012/000269)., Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence des Mycobactéries et de la Résistance aux Antituberculeux [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux, Bactériologie-Hygiène [CHU Pitié-Salpêtrière] ], and CHU Pitié-Salpêtrière [APHP]

Subjects
0301 basic medicine, MESH: Mycobacterium tuberculosis, DNA Mutational Analysis, Mutant, Antitubercular Agents, medicine.disease_cause, DNA gyrase, MESH: Recombinant Proteins, Suppression, Genetic, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Pharmacology (medical), MESH: DNA Mutational Analysis, MESH: Suppression, Genetic, MESH: Inhibitory Concentration 50, Mutation, MESH: Microbial Sensitivity Tests, biology, Chemistry, MESH: Escherichia coli, Recombinant Proteins, 3. Good health, MESH: Mutagenesis, Site-Directed, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, DNA Gyrase, DNA supercoil, Fluoroquinolones, medicine.drug, MESH: DNA Gyrase, Microbiology (medical), 030106 microbiology, Mutation, Missense, Microbial Sensitivity Tests, Microbiology, Mycobacterium tuberculosis, Inhibitory Concentration 50, 03 medical and health sciences, Drug Resistance, Bacterial, MESH: Drug Resistance, Bacterial, Escherichia coli, medicine, Humans, Pharmacology, MESH: Mutation, Missense, MESH: Humans, Mutagenesis, MESH: Fluoroquinolones, biology.organism_classification, MESH: Antitubercular Agents, Mutagenesis, Site-Directed, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Ofloxacin
Abstract

International audience; OBJECTIVES:Resistance to fluoroquinolones (FQs) in Mycobacterium tuberculosis (Mtb) is mainly due to mutations in DNA gyrase (GyrA2B2), with the most common substitutions located at positions 90 and 94 in GyrA. Two clinical MDR Mtb (MDR-TB) strains harbouring an A90E or D94N substitution in GyrA were found to be surprisingly susceptible to FQs (ofloxacin MIC ≤2 mg/L). We studied the impact of the additional GyrA substitutions found in these strains (T80A and T80A + A90G, respectively) on FQ susceptibility.METHODS:Mutants of interest were generated by site-specific mutagenesis of GyrA alleles. WT and mutant TB DNA gyrase subunits were overexpressed in Escherichia coli and purified, and the in vitro susceptibility to FQs of their DNA supercoiling reaction was studied.RESULTS:IC50s of mutant gyrase complexes bearing GyrA D94N and A90E were 3- to 36-fold higher than WT IC50s, whereas IC50s of gyrase bearing T80A + A90G + D94N and T80A + A90E were close to the WT IC50s.CONCLUSIONS:We demonstrated that substitutions T80A and A90G restore FQ susceptibility when associated with a substitution implicated in high-level FQ resistance. Line probe assay misclassification of MDR-TB strains as pre-XDR or XDR can be corrected by sequence analysis of gyrA.

Published
2016