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Paradoxical Hypersusceptibility of Drug-resistant Mycobacterium tuberculosis to β-lactam Antibiotics

Authors: Keira A. Cohen, Tal El-Hay, Kelly L. Wyres, Omer Weissbrod, Vanisha Munsamy, Chen Yanover, Ranit Aharonov, Oded Shaham, Thomas C. Conway, Yaara Goldschmidt, William R. Bishai, Alexander S. Pym

Abstract

Mycobacterium tuberculosis (M. tuberculosis) is considered innately resistant to β-lactam antibiotics. However, there is evidence that susceptibility to β-lactam antibiotics in combination with β–lactamase inhibitors is variable among clinical isolates, and these may present therapeutic options for drug-resistant cases. Here we report our investigation of susceptibility to β-lactam/β–lactamase inhibitor combinations among clinical isolates of M. tuberculosis, and the use of comparative genomics to understand the observed heterogeneity in susceptibility. Eighty-nine South African clinical isolates of varying first and second-line drug susceptibility patterns and two reference strains of M. tuberculosis underwent minimum inhibitory concentration (MIC) determination to two β-lactams: amoxicillin and meropenem, both alone and in combination with clavulanate, a β–lactamase inhibitor. 41/91 (45%) of tested isolates were found to be hypersusceptible to amoxicillin/clavulanate relative to reference strains, including 14/24 (58%) of multiple drug-resistant (MDR) and 22/38 (58%) of extensively drug-resistant (XDR) isolates. Genome-wide polymorphisms identified using whole-genome sequencing were used in a phylogenetically-aware linear mixed model to identify polymorphisms associated with amoxicillin/clavulanate susceptibility. Susceptibility to amoxicillin/clavulanate was over-represented among isolates within a specific clade (LAM4), in particular among XDR strains. Twelve sets of polymorphisms were identified as putative markers of amoxicillin/clavulanate susceptibility, five of which were confined solely to LAM4. Within the LAM4 clade, ‘paradoxical hypersusceptibility’ to amoxicillin/clavulanate has evolved in parallel to first and second-line drug resistance. Given the high prevalence of LAM4 among XDR TB in South Africa, our data support an expanded role for β-lactam/β-lactamase inhibitor combinations for treatment of drug-resistant M. tuberculosis.

Abbreviations

XDR, extensively drug resistant; MIC, minimum inhibitory concentration; MDR, multidrug resistant; SNP, single nucleotide polymorphism; SNV, single nucleotide variant; WGS, whole-genome sequencing

Keywords

tuberculosis; Multi-drug resistant (MDR); Extensively drug resistant (XDR); Beta-lactam antibiotics; Antimicrobial chemotherapy; pks12; Recombination

Citation: Keira A. Cohen, Tal El-Hay, Kelly L. Wyres, Omer Weissbrod, Vanisha Munsamy Paradoxical Hypersusceptibility of Drug-resistant Mycobacterium tuberculosis to β-lactam Antibiotics doi:10.1016/j.ebiom.2016.05.041

Received: 10 March 2016 Revised: 18 May 2016 Accepted: 31 May 2016 Available online: 1 June 2016

Copyright: © 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Funding Information

KAC was supported by T32HL007633 of the National Heart, Lung and Blood Institute. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Open access publication of this article has been made possible through support from the Victor Daitz Information Gateway, an initiative of the Victor Daitz Foundation and the University of KwaZulu-Natal.

Conflicts of Interest

None declared.

Acknowledgements

We thank Eyal Privman for helpful discussions. We thank Anna Trigos for assistance with the gene-content analysis. We would like to thank Nonkqubela Bantubani of the Medical Research Council (MRC) in Durban, in addition to Drs. Max O′Donnell and Nesri Padayatchi for contributing clinical isolates of M. tuberculosis, which were used in this study. Lastly, we would like to thank Prof. Koleka P. Mlisana and Dr. Nomonde R. Mvelase of the KwaZulu-Natal National Health Laboratory Service and Dr. Gyanu Lamichhane for providing nitrocefin.

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