8 results on '"Serral, F."'
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2. Fever-like temperature impacts on Staphylococcus aureus and Pseudomonas aeruginosa interaction, physiology, and virulence both in vitro and in vivo .
- Author
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Solar Venero EC, Galeano MB, Luqman A, Ricardi MM, Serral F, Fernandez Do Porto D, Robaldi SA, Ashari B, Munif TH, Egoburo DE, Nemirovsky S, Escalante J, Nishimura B, Ramirez MS, Götz F, and Tribelli PM
- Abstract
Background: Staphylococcus aureus and Pseudomonas aeruginosa cause a wide variety of bacterial infections and coinfections, showing a complex interaction that involves the production of different metabolites and metabolic changes. Temperature is a key factor for bacterial survival and virulence and within the host, bacteria could be exposed to an increment in temperature during fever development. We analyzed the previously unexplored effect of fever-like temperatures (39°C) on S. aureus USA300 and P. aeruginosa PAO1 microaerobic mono- and co-cultures compared with 37°C, by using RNAseq and physiological assays including in-vivo experiments., Results: In general terms both temperature and co-culturing had a strong impact on both PA and SA with the exception of the temperature response of monocultured PA. We studied metabolic and virulence changes on both species. Altered metabolic features at 39°C included arginine biosynthesis and the periplasmic glucose oxidation in S. aureus and P. aeruginosa monocultures respectively. When PA co-cultures were exposed at 39°C they upregulated ethanol oxidation related genes along with an increment in organic acid accumulation. Regarding virulence factors, monocultured SA showed an increase in the mRNA expression of the agr operon and hld, pmsα and pmsβ genes at 39°C. Supported by mRNA data, we performed physiological experiments and detected and increment in hemolysis, staphylxantin production and a decrease in biofilm formation at 39°C. On the side of PA monocultures, we observed increase in extracellular lipase and protease and biofilm formation at 39°C along with a decrease in motility in correlation with changes observed at mRNA abundance. Additionally, we assessed host-pathogen interaction both in-vitro and in-vivo . S. aureus monocultured at 39°C showed a decrease in cellular invasion and an increase in IL-8 -but not in IL-6- production by A549 cell line. PA also decreased its cellular invasion when monocultured at 39°C and did not induce any change in IL-8 or IL-6 production. PA strongly increased cellular invasion when co-cultured at 37°C and 39°C. Finally, we observed increased lethality in mice intranasally inoculated with S. aureus monocultures pre-incubated at 39°C and even higher levels when inoculated with co-cultures. The bacterial burden for P. aeruginosa was higher in liver when the mice were infected with co-cultures previously incubated at 39°C comparing with 37°C., Conclusion: Our results highlight a relevant change in the virulence of bacterial opportunistic pathogens exposed to fever-like temperatures in presence of competitors, opening new questions related to bacteria-bacteria and host-pathogen interactions and coevolution.
- Published
- 2023
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3. Pathway Driven Target Selection in Klebsiella pneumoniae : Insights Into Carbapenem Exposure.
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Serral F, Pardo AM, Sosa E, Palomino MM, Nicolás MF, Turjanski AG, Ramos PIP, and Fernández Do Porto D
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- Anti-Bacterial Agents therapeutic use, Carbapenems pharmacology, Carbapenems therapeutic use, Humans, Klebsiella pneumoniae genetics, Klebsiella pneumoniae metabolism, Carbapenem-Resistant Enterobacteriaceae, Klebsiella Infections drug therapy
- Abstract
Carbapenem-resistant Klebsiella pneumoniae (CR-KP) represents an emerging threat to public health. CR-KP infections result in elevated morbidity and mortality. This fact, coupled with their global dissemination and increasingly limited number of therapeutic options, highlights the urgency of novel antimicrobials. Innovative strategies linking genome-wide interrogation with multi-layered metabolic data integration can accelerate the early steps of drug development, particularly target selection. Using the BioCyc ontology, we generated and manually refined a metabolic network for a CR-KP, K. pneumoniae Kp13. Converted into a reaction graph, we conducted topological-based analyses in this network to prioritize pathways exhibiting druggable features and fragile metabolic points likely exploitable to develop novel antimicrobials. Our results point to the aptness of previously recognized pathways, such as lipopolysaccharide and peptidoglycan synthesis, and casts light on the possibility of targeting less explored cellular functions. These functions include the production of lipoate, trehalose, glycine betaine, and flavin, as well as the salvaging of methionine. Energy metabolism pathways emerged as attractive targets in the context of carbapenem exposure, targeted either alone or in conjunction with current therapeutic options. These results prompt further experimental investigation aimed at controlling this highly relevant pathogen., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Serral, Pardo, Sosa, Palomino, Nicolás, Turjanski, Ramos and Fernández Do Porto.)
- Published
- 2022
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4. Identification of Potential Kinase Inhibitors within the PI3K/AKT Pathway of Leishmania Species.
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Ochoa R, Ortega-Pajares A, Castello FA, Serral F, Fernández Do Porto D, Villa-Pulgarin JA, Varela-M RE, and Muskus C
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- Binding Sites, Drug Evaluation, Preclinical, Glycogen Synthase Kinase 3 antagonists & inhibitors, Glycogen Synthase Kinase 3 metabolism, Molecular Docking Simulation, Phosphatidylinositol 3-Kinases metabolism, Protein Interaction Maps, Protein Kinases chemistry, Proto-Oncogene Proteins c-akt metabolism, Protozoan Proteins antagonists & inhibitors, Protozoan Proteins chemistry, Leishmania drug effects, Leishmania metabolism, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Protein Kinases metabolism, Protozoan Proteins metabolism
- Abstract
Leishmaniasis is a public health disease that requires the development of more effective treatments and the identification of novel molecular targets. Since blocking the PI3K/AKT pathway has been successfully studied as an effective anticancer strategy for decades, we examined whether the same approach would also be feasible in Leishmania due to their high amount and diverse set of annotated proteins. Here, we used a best reciprocal hits protocol to identify potential protein kinase homologues in an annotated human PI3K/AKT pathway. We calculated their ligandibility based on available bioactivity data of the reported homologues and modelled their 3D structures to estimate the druggability of their binding pockets. The models were used to run a virtual screening method with molecular docking. We found and studied five protein kinases in five different Leishmania species, which are AKT, CDK, AMPK, mTOR and GSK3 homologues from the studied pathways. The compounds found for different enzymes and species were analysed and suggested as starting point scaffolds for the design of inhibitors. We studied the kinases' participation in protein-protein interaction networks, and the potential deleterious effects, if inhibited, were supported with the literature. In the case of Leishmania GSK3, an inhibitor of its human counterpart, prioritized by our method, was validated in vitro to test its anti- Leishmania activity and indirectly infer the presence of the enzyme in the parasite. The analysis contributes to improving the knowledge about the presence of similar signalling pathways in Leishmania , as well as the discovery of compounds acting against any of these kinases as potential molecular targets in the parasite.
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- 2021
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5. From Genome to Drugs: New Approaches in Antimicrobial Discovery.
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Serral F, Castello FA, Sosa EJ, Pardo AM, Palumbo MC, Modenutti C, Palomino MM, Lazarowski A, Auzmendi J, Ramos PIP, Nicolás MF, Turjanski AG, Martí MA, and Fernández Do Porto D
- Abstract
Decades of successful use of antibiotics is currently challenged by the emergence of increasingly resistant bacterial strains. Novel drugs are urgently required but, in a scenario where private investment in the development of new antimicrobials is declining, efforts to combat drug-resistant infections become a worldwide public health problem. Reasons behind unsuccessful new antimicrobial development projects range from inadequate selection of the molecular targets to a lack of innovation. In this context, increasingly available omics data for multiple pathogens has created new drug discovery and development opportunities to fight infectious diseases. Identification of an appropriate molecular target is currently accepted as a critical step of the drug discovery process. Here, we review how diverse layers of multi-omics data in conjunction with structural/functional analysis and systems biology can be used to prioritize the best candidate proteins. Once the target is selected, virtual screening can be used as a robust methodology to explore molecular scaffolds that could act as inhibitors, guiding the development of new drug lead compounds. This review focuses on how the advent of omics and the development and application of bioinformatics strategies conduct a "big-data era" that improves target selection and lead compound identification in a cost-effective and shortened timeline., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Serral, Castello, Sosa, Pardo, Palumbo, Modenutti, Palomino, Lazarowski, Auzmendi, Ramos, Nicolás, Turjanski, Martí and Fernández Do Porto.)
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- 2021
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6. Five-year microevolution of a multidrug-resistant Mycobacterium tuberculosis strain within a patient with inadequate compliance to treatment.
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Fernandez Do Porto DA, Monteserin J, Campos J, Sosa EJ, Matteo M, Serral F, Yokobori N, Benevento AF, Poklepovich T, Pardo A, Wainmayer I, Simboli N, Castello F, Paul R, Martí M, López B, Turjanski A, and Ritacco V
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- Adult, Antitubercular Agents pharmacology, Antitubercular Agents therapeutic use, Argentina, Drug Resistance, Multiple, Bacterial drug effects, Female, Humans, Isoniazid therapeutic use, Medication Adherence, Microbial Sensitivity Tests, Mutation, Mycobacterium tuberculosis isolation & purification, Phylogeny, Pyrazinamide therapeutic use, Rifampin therapeutic use, Streptomycin pharmacology, Tuberculosis, Pulmonary drug therapy, Tuberculosis, Pulmonary microbiology, Whole Genome Sequencing, Drug Resistance, Multiple, Bacterial genetics, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis genetics, Tuberculosis, Multidrug-Resistant drug therapy, Tuberculosis, Multidrug-Resistant microbiology
- Abstract
Background: Whole-genome sequencing has shown that the Mycobacterium tuberculosis infection process can be more heterogeneous than previously thought. Compartmentalized infections, exogenous reinfections, and microevolution are manifestations of this clonal complexity. The analysis of the mechanisms causing the microevolution -the genetic variability of M. tuberculosis at short time scales- of a parental strain into clonal variants with a patient is a relevant issue that has not been yet completely addressed. To our knowledge, a whole genome sequence microevolution analysis in a single patient with inadequate adherence to treatment has not been previously reported., Case Presentation: In this work, we applied whole genome sequencing analysis for a more in-depth analysis of the microevolution of a parental Mycobacterium tuberculosis strain into clonal variants within a patient with poor treatment compliance in Argentina. We analyzed the whole-genome sequence of 8 consecutive Mycobacterium tuberculosis isolates obtained from a patient within 57-months of intermittent therapy. Nineteen mutations (9 short-term, 10 fixed variants) emerged, most of them associated with drug resistance. The first isolate was already resistant to isoniazid, rifampicin, and streptomycin, thereafter the strain developed resistance to fluoroquinolones and pyrazinamide. Surprisingly, isolates remained susceptible to the pro-drug ethionamide after acquiring a frameshift mutation in ethA, a gene required for its activation. We also found a novel variant, (T-54G), in the 5' untranslated region of whiB7 (T-54G), a region allegedly related to kanamycin resistance. Notably, discrepancies between canonical and phage-based susceptibility testing to kanamycin were previously found for the isolate harboring this mutation. In our patient, microevolution was mainly driven by drug selective pressure. Rare short-term mutations fixed together with resistance-conferring mutations during therapy., Conclusions: This report highlights the relevance of whole-genome sequencing analysis in the clinic for characterization of pre-XDR and MDR resistance profile, particularly in patients with incomplete and/or intermittent treatment.
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- 2021
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7. Methylobacterium sp. 2A Is a Plant Growth-Promoting Rhizobacteria That Has the Potential to Improve Potato Crop Yield Under Adverse Conditions.
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Grossi CEM, Fantino E, Serral F, Zawoznik MS, Fernandez Do Porto DA, and Ulloa RM
- Abstract
A Gram-negative pink-pigmented bacillus (named 2A) was isolated from Solanum tuberosum L. cv. Desirée plants that were strikingly more developed, presented increased root hair density, and higher biomass than other potato lines of the same age. The 16S ribosomal DNA sequence, used for comparative gene sequence analysis, indicated that strain 2A belongs to the genus Methylobacterium . Nucleotide identity between Methylobacterium sp. 2A sequenced genome and the rest of the species that belong to the genus suggested that this species has not been described so far. In vitro, potato plants inoculated with Methylobacterium sp. 2A had a better performance when grown under 50 mM NaCl or when infected with Phytophthora infestans . We inoculated Methylobacterium sp. 2A in Arabidopsis thaliana roots and exposed these plants to salt stress (75 mM NaCl). Methylobacterium sp. 2A-inoculated plants, grown in control or salt stress conditions, displayed a higher density of lateral roots (p < 0.05) compared to noninoculated plants. Moreover, under salt stress, they presented a higher number of leaves and larger rosette diameter. In dual confrontation assays, Methylobacterium sp. 2A displayed biocontrol activity against P. infestans , Botrytis cinerea , and Fusarium graminearum , but not against Rhizoctonia solani , and Pythium dissotocum . In addition, we observed that Methylobacterium sp. 2A diminished the size of necrotic lesions and reduced chlorosis when greenhouse potato plants were infected with P. infestans . Methylobacterium sp. 2A produces indole acetic acid, solubilizes mineral phosphate and is able to grow in a N
2 free medium. Whole-genome sequencing revealed metabolic pathways associated with its plant growth promoter capacity. Our results suggest that Methylobacterium sp. 2A is a plant growth-promoting rhizobacteria (PGPR) that can alleviate salt stress, and restricts P. infestans infection in potato plants, emerging as a potential strategy to improve crop management., (Copyright © 2020 Grossi, Fantino, Serral, Zawoznik, Fernandez Do Porto and Ulloa.)- Published
- 2020
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8. Prioritisation of potential drug targets against Bartonella bacilliformis by an integrative in-silico approach.
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Farfán-López M, Espinoza-Culupú A, García-de-la-Guarda R, Serral F, Sosa E, Palomino MM, and Fernández Do Porto DA
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- Bartonella bacilliformis genetics, Bartonella bacilliformis isolation & purification, DNA, Bacterial genetics, DNA, Bacterial isolation & purification, Genomics, Humans, Polymerase Chain Reaction, Anti-Bacterial Agents therapeutic use, Bartonella Infections drug therapy, Bartonella bacilliformis drug effects
- Abstract
BACKGROUND Carrion's disease (CD) is a neglected biphasic illness caused by Bartonella bacilliformis, a Gram-negative bacteria found in the Andean valleys. The spread of resistant strains underlines the need for novel antimicrobials against B. bacilliformis and related bacterial pathogens. OBJECTIVE The main aim of this study was to integrate genomic-scale data to shortlist a set of proteins that could serve as attractive targets for new antimicrobial discovery to combat B. bacilliformis. METHODS We performed a multidimensional genomic scale analysis of potential and relevant targets which includes structural druggability, metabolic analysis and essentiality criteria to select proteins with attractive features for drug discovery. FINDINGS We shortlisted seventeen relevant proteins to develop new drugs against the causative agent of Carrion's disease. Particularly, the protein products of fabI, folA, aroA, trmFO, uppP and murE genes, meet an important number of desirable features that make them attractive targets for new drug development. This data compendium is freely available as a web server (http://target.sbg.qb.fcen.uba.ar/). MAIN CONCLUSION This work represents an effort to reduce the costs in the first phases of B. bacilliformis drug discovery.
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- 2020
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