Journal article

Predicting nitroimidazole antibiotic resistance mutations in Mycobacterium tuberculosis with protein engineering

Brendon M Lee, Liam K Harold, Deepak V Almeida, Livnat Afriat-Jurnou, Htin Lin Aung, Brian M Forde, Kiel Hards, Sacha J Pidot, F Hafna Ahmed, A Elaaf Mohamed, Matthew C Taylor, Nicholas P West, Timothy P Stinear, Chris Greening, Scott A Beatson, Eric L Nuermberger, Gregory M Cook, Colin J Jackson

PLOS PATHOGENS | PUBLIC LIBRARY SCIENCE | Published : 2020

Abstract

Our inability to predict which mutations could result in antibiotic resistance has made it difficult to rapidly identify the emergence of resistance, identify pre-existing resistant populations, and manage our use of antibiotics to effectively treat patients and prevent or slow the spread of resistance. Here we investigated the potential for resistance against the new antitubercular nitroimidazole prodrugs pretomanid and delamanid to emerge in Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). Deazaflavin-dependent nitroreductase (Ddn) is the only identified enzyme within M. tuberculosis that activates these prodrugs, via an F420H2-dependent reaction. We show that the nati..

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Grants

Awarded by ARC DECRA Fellowship


Awarded by U.S. National Institutes of Health


Awarded by NHMRC


Funding Acknowledgements

This work was supported by by NHMRC Project Grant APP1128929 (to C. J. J., C. G., and G. M. C.). In addition, this work was supported by an ARC DECRA Fellowship DE170100310, and NHMRC New Investigator Grant APP1139832 (to C. G.). SAB is supported by an NHMRC Career Development Fellowship GNT1090456 (to SAB). DVA and ELN acknowledge the support of the U.S. National Institutes of Health (R01-AI111992). Websites of funders: https://www.nhmrc.gov.au/https://www.nhmrc.gov.au/https://www.nih.gov/The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.