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), known for its innate resistance to β-lactam antibiotics, exhibits variable susceptibility to β-lactam/β-lactamase inhibitor combinations among clinical isolates. This presents potential therapeutic options for drug-resistant cases. Our study investigates the susceptibility of clinical M. tuberculosis isolates to β-lactam/β-lactamase inhibitor combinations and utilizes comparative genomics to understand the observed heterogeneity. We evaluated 89 South African clinical isolates with varying drug susceptibility patterns, along with two reference strains, using minimum inhibitory concentration (MIC) determination for amoxicillin and meropenem alone and in combination with clavulanate. Results showed that 41 out of 91 tested isolates (45%) were hypersusceptible to amoxicillin/clavulanate compared to reference strains. This hypersusceptibility was prominent among multiple drug-resistant (MDR) and extensively drug-resistant (XDR) isolates, with 58% in each category. Comparative genomics analysis using whole-genome sequencing identified polymorphisms associated with amoxicillin/clavulanate susceptibility, with a specific clade (LAM4) showing over-representation of susceptibility, especially among XDR strains. We identified twelve sets of polymorphisms, including five unique to LAM4, as putative markers of amoxicillin/clavulanate susceptibility. Notably, within the LAM4 clade, a phenomenon of "paradoxical hypersusceptibility" to amoxicillin/clavulanate has evolved alongside first and second-line drug resistance. Considering the high prevalence of LAM4 among XDR TB in South Africa, our findings support the expanded use of β-lactam/β-lactamase inhibitor combinations for treating 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.
