Contribution of Efflux to the Emergence of Isoniazid and Multidrug Resistance in Mycobacterium tuberculosis
Diana Machado,Isabel Couto,João Perdigão,Liliana Rodrigues,Isabel Portugal,Pedro V. Baptista,Bruno Veigas,Leonard Amaral,Miguel Viveiros +8 more
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TLDR
Results support the hypothesis that activity of efflux pumps allows the maintenance of an isoniazid resistant population in a sub-optimally treated patient and should be considered in the development of new therapeutic strategies for preventing the emergence of MDR-TB during treatment.Abstract:
Multidrug resistant (MDR) tuberculosis is caused by Mycobacterium tuberculosis resistant to isoniazid and rifampicin, the two most effective drugs used in tuberculosis therapy. Here, we investigated the mechanism by which resistance towards isoniazid develops and how overexpression of efflux pumps favors accumulation of mutations in isoniazid targets, thus establishing a MDR phenotype. The study was based on the in vitro induction of an isoniazid resistant phenotype by prolonged serial exposure of M. tuberculosis strains to the critical concentration of isoniazid employed for determination of drug susceptibility testing in clinical isolates. Results show that susceptible and rifampicin monoresistant strains exposed to this concentration become resistant to isoniazid after three weeks; and that resistance observed for the majority of these strains could be reduced by means of efflux pumps inhibitors. RT-qPCR assessment of efflux pump genes expression showed overexpression of all tested genes. Enhanced real-time efflux of ethidium bromide, a common efflux pump substrate, was also observed, showing a clear relation between overexpression of the genes and increased efflux pump function. Further exposure to isoniazid resulted in the selection and stabilization of spontaneous mutations and deletions in the katG gene along with sustained increased efflux activity. Together, results demonstrate the relevance of efflux pumps as one of the factors of isoniazid resistance in M. tuberculosis. These results support the hypothesis that activity of efflux pumps allows the maintenance of an isoniazid resistant population in a sub-optimally treated patient from which isoniazid genetically resistant mutants emerge. Therefore, the use of inhibitors of efflux should be considered in the development of new therapeutic strategies for preventing the emergence of MDR-TB during treatment.read more
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The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis
Keertan Dheda,Tawanda Gumbo,Gary Maartens,Kelly E. Dooley,Ruth McNerney,Megan Murray,Jennifer Furin,Edward A. Nardell,Leslie London,Erica Lessem,Grant Theron,Paul D. van Helden,Stefan Niemann,Matthias Merker,David W. Dowdy,Annelies Van Rie,Annelies Van Rie,Gilman Kit Hang Siu,Jotam G. Pasipanodya,Camilla Rodrigues,Taane G. Clark,F. A. Sirgel,Aliasgar Esmail,Hsien-Ho Lin,Sachin R Atre,H. Simon Schaaf,Kwok Chiu Chang,Christoph Lange,Payam Nahid,Zarir F Udwadia,C. Robert Horsburgh,Gavin J. Churchyard,Gavin J. Churchyard,Dick Menzies,Anneke C. Hesseling,Eric L. Nuermberger,Helen McIlleron,Kevin P. Fennelly,Eric Goemaere,Ernesto Jaramillo,Marcus Low,Carolina Morán Jara,Nesri Padayatchi,Robin M. Warren +43 more
TL;DR: Several lines of evidence suggest that alternative mechanisms-including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions-are likely crucial to the pathogenesis of drug-resistant tuberculosis.
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Multidrug Efflux Pumps in Staphylococcus aureus: an Update
TL;DR: The current knowledge on MDR efflux pumps and their intricate regulatory network in Staphylococcus aureus, a major pathogen, responsible from mild to life-threatening infections is reviewed and particular emphasis is given to the potential role that S. a Aureus MDRefflux pumps, either chromosomal or plasmid-encoded, have on resistance towards different antimicrobial agents and on the selection of drug - resistant strains.
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Antimicrobial resistance in Mycobacterium tuberculosis: mechanistic and evolutionary perspectives
Sebastian M. Gygli,Sebastian M. Gygli,Sonia Borrell,Sonia Borrell,Andrej Trauner,Andrej Trauner,Sebastien Gagneux,Sebastien Gagneux +7 more
TL;DR: Although the genetic diversity of M. tuberculosis is low compared to other pathogenic bacteria, the strain genetic background has been demonstrated to influence multiple aspects in the evolution of drug resistance.
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Global control of tuberculosis: from extensively drug-resistant to untreatable tuberculosis.
Keertan Dheda,Tawanda Gumbo,Neel R. Gandhi,Megan Murray,Grant Theron,Zarir F Udwadia,G. B. Migliori,Robin M. Warren +7 more
TL;DR: The epidemiology, pathogenesis, diagnosis, management, implications for health-care workers, and ethical and medicolegal aspects of extensively drug-resistant tuberculosis and other resistant strains are discussed.
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Evolution of drug resistance in Mycobacterium tuberculosis: a review on the molecular determinants of resistance and implications for personalized care
Navisha Dookie,Santhuri Rambaran,Nesri Padayatchi,Nesri Padayatchi,Sharana Mahomed,Kogieleum Naidoo,Kogieleum Naidoo +6 more
TL;DR: Advances in sequencing technology will help devise better molecular diagnostics for more effective DR-TB management enabling personalized treatment, and will facilitate the development of new drugs aimed at improving outcomes of patients with this disease.
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Journal ArticleDOI
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TL;DR: Substitution of a limited number of highly conserved aminoacids encoded by the rpoB gene appears to be the molecular mechanism responsible for "single step" high-level resistance to rifampicin in M tuberculosis, a marker of multidrug-resistant tuberculosis.
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Proposal for Standardization of Optimized Mycobacterial Interspersed Repetitive Unit-Variable-Number Tandem Repeat Typing of Mycobacterium tuberculosis
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