Journal article

Empirical ways to identify novel Bedaquiline resistance mutations in AtpE

Malancha Karmakar, Carlos HM Rodrigues, Kathryn E Holt, Sarah J Dunstan, Justin Denholm, David B Ascher

PLOS ONE | PUBLIC LIBRARY SCIENCE | Published : 2019

Abstract

Clinical resistance against Bedaquiline, the first new anti-tuberculosis compound with a novel mechanism of action in over 40 years, has already been detected in Mycobacterium tuberculosis. As a new drug, however, there is currently insufficient clinical data to facilitate reliable and timely identification of genomic determinants of resistance. Here we investigate the structural basis for M. tuberculosis associated bedaquiline resistance in the drug target, AtpE. Together with the 9 previously identified resistance-associated variants in AtpE, 54 non-resistance-associated mutations were identified through comparisons of bedaquiline susceptibility across 23 different mycobacterial species. C..

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Grants

Awarded by Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG)


Awarded by Jack Brockhoff Foundation


Awarded by C. J. Martin Research Fellowship from the National Health and Medical Research Council (NHMRC) of Australia


Awarded by NHMRC Australia


Funding Acknowledgements

M.K was funded by the Melbourne Research Scholarship. D.B.A was funded by a Newton Fund RCUK-CONFAP Grant awarded by The Medical Research Council (MRC) and Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG) (MR/M026302/1), the Jack Brockhoff Foundation (JBF 4186, 2016), and a C. J. Martin Research Fellowship from the National Health and Medical Research Council (NHMRC) of Australia (APP1072476). The Vietnam genomic dataset was funded by a NHMRC Australia grant (APP1056689) to SJD and KEH. This work was supported in part by the Victorian Government's OIS Program. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.