Search

Showing total 3 results
Start Over Topic antitubercular agents Publication Year Range Last 50 years
3 results

1. Vitamins Based Novel Target Pathways/Molecules as Possible Emerging Drug Targets for the Management of Tuberculosis.

Author

Sharma A, Jain K, and Flora SJS

Subjects
Drug Design, Humans, Molecular Targeted Therapy, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis enzymology, Mycobacterium tuberculosis genetics, Tuberculosis, Pulmonary drug therapy, Antitubercular Agents pharmacology, Enzyme Inhibitors pharmacology, Vitamins biosynthesis
Abstract

Background: Tuberculosis (TB) is a deadly infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb). Approximately, 1.8 and 1.3 million people are infected and die, from TB each year as estimated by the World Health Organization. Due to increase in the incidence of drug-resistant strains of Mtb, there is an urgent need to accelerate research which focuses on the development of new drugs with novel mechanism of action that can treat both drugsensitive and resistant TB infections., Objective: The purpose of this review study was to describe vitamins as drug target that can be explored to develop new anti tubercular drugs that can treat both drug-sensitive and resistant TB infections., Method: The methodological approaches include literature review which is performed in the databases like PubMed, Web of Science, Scopus, Springer and Science Direct, etc. On the basis of evaluation of literature sources, the review was complied., Results: This review study demonstrated that vitamins biosynthesis pathway could be used in the development of novel drug targets. Further sequencing of the Mtb genome facilitated research in target identification and validation that make possible the discovery of novel anti-TB agent with new mechanisms of action. Several compounds were identified, which target vitamin biosynthesis pathway /enzymes. Some other new targets were also identified and can be explored for the identification of novel structural moiety., Conclusion: Further exploration of these compounds which have been identified to target these vitamins related novel target pathways /molecules could led to the development of antitubercular drug which can be used in the treatment of drug sensitive and resistant TB., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Published
2018
Full Text
View/download PDF

2. 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

3. 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