Acquired Resistance of Mycobacterium tuberculosis to Bedaquiline
Koen Andries,Cristina Villellas,Nele Coeck,Kim Thys,Tom Gevers,Luc Vranckx,Nacer Lounis,Bouke C. de Jong,Anil Koul +8 more
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TLDR
It is reported that non-target based resistance to BDQ, and cross-resistance to clofazimine (CFZ), is due to mutations in Rv0678, a transcriptional repressor of the genes encoding the MmpS5-MmpL5 efflux pump.Abstract:
Bedaquiline (BDQ), an ATP synthase inhibitor, is the first drug to be approved for treatment of multi-drug resistant tuberculosis in decades. In vitro resistance to BDQ was previously shown to be due to target-based mutations. Here we report that non-target based resistance to BDQ, and cross-resistance to clofazimine (CFZ), is due to mutations in Rv0678, a transcriptional repressor of the genes encoding the MmpS5-MmpL5 efflux pump. Efflux-based resistance was identified in paired isolates from patients treated with BDQ, as well as in mice, in which it was confirmed to decrease bactericidal efficacy. The efflux inhibitors verapamil and reserpine decreased the minimum inhibitory concentrations of BDQ and CFZ in vitro, but verapamil failed to increase the bactericidal effect of BDQ in mice and was unable to reverse efflux-based resistance in vivo. Cross-resistance between BDQ and CFZ may have important clinical implications.read more
Citations
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Multidrug efflux pumps: structure, function and regulation
Dijun Du,Xuan Wang-Kan,Arthur Neuberger,Hendrik W. van Veen,Klaas M. Pos,Laura J. V. Piddock,Ben F. Luisi +6 more
TL;DR: Recent advances that have increased understanding of the structures and molecular mechanisms of multidrug efflux pumps in bacteria are described, suggesting opportunities for countering their activities.
Journal ArticleDOI
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.
Journal ArticleDOI
Rapid determination of anti-tuberculosis drug resistance from whole-genome sequences
Francesc Coll,Ruth McNerney,Mark D. Preston,José Afonso Guerra-Assunção,Andrew Warry,Grant A. Hill-Cawthorne,Grant A. Hill-Cawthorne,Kim Mallard,Mridul Nair,Anabela Miranda,Adriana Alves,João Perdigão,Miguel Viveiros,Isabel Portugal,Zahra Hasan,Rumina Hasan,Judith R. Glynn,Nigel Martin,Arnab Pain,Taane G. Clark +19 more
TL;DR: A library predictive of DR for 15 anti-tuberculosis drugs was compiled and validated for 11 of them using genomic-phenotypic data from 792 strains, and in silico diagnostic accuracy was superior to some commercial diagnostics and alternative databases.
Journal ArticleDOI
Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis.
Alexander S. Pym,Andreas H. Diacon,Shenjie Tang,Francesca Conradie,Manfred Danilovits,Charoen Chuchottaworn,Irina Vasilyeva,Koen Andries,Nyasha Bakare,Tine De Marez,Myriam Haxaire-Theeuwes,Nacer Lounis,Paul Meyvisch,Ben Van Baelen,Rolf van Heeswijk,Brian Dannemann +15 more
TL;DR: Addition of bedaquiline to a background regimen was well tolerated and led to good outcomes in this clinically relevant patient cohort with MDR-TB.
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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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