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Determination of Potentially Novel Compensatory Mutations in rpoC Associated with Rifampin Resistance and rpoB Mutations in Mycobacterium tuberculosis Clinical Isolates from Peru

Vargas, AP; Rios, AA; Grandjean, L; Kirwan, DE; Gilman, RH; Sheen, P; Zimic, MJ; (2020) Determination of Potentially Novel Compensatory Mutations in rpoC Associated with Rifampin Resistance and rpoB Mutations in Mycobacterium tuberculosis Clinical Isolates from Peru. International Journal of Mycobacteriology , 9 (2) pp. 121-137. 10.4103/ijmy.ijmy_27_20. Green open access

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Abstract

BACKGROUND: Rifampicin (RIF) resistance in Mycobacterium tuberculosis is frequently caused by mutations in the rpoB gene. These mutations are associated with a fitness cost, which can be overcome by compensatory mutations in other genes, among which rpoC may be the most important. We analyzed 469 Peruvian M. tuberculosis clinical isolates to identify compensatory mutations in rpoC/rpoA associated with RIF resistance. METHODS: The M. tuberculosis isolates were collected and tested for RIF susceptibility and spoligotyping. Samples were sequenced and aligned to the reference genome to identify mutations. By analyzing the sequences and the metadata, we identified a list of rpoC mutations exclusively associated with RIF resistance and mutations in rpoB. We then evaluated the distribution of these mutations along the protein sequence and tridimensional structure. RESULTS: One hundred and twenty-five strains were RIF susceptible and 346 were resistant. We identified 35 potential new compensatory mutations, some of which were distributed on the interface surface between rpoB and rpoC, arising in clusters and suggesting the presence of hotspots for compensatory mutations. CONCLUSIONS: This study identifies 35 putative novel compensatory mutations in the β' subunit of M. tuberculosis RNApol. Six of these (S428T, L507V, A734V, I997V, and V1252LM) are considered most likely to have a compensatory role, as they fall in the interaction zone of the two subunits and the mutation did not lead to any change in the protein's physical–chemical properties.

Type: Article
Title: Determination of Potentially Novel Compensatory Mutations in rpoC Associated with Rifampin Resistance and rpoB Mutations in Mycobacterium tuberculosis Clinical Isolates from Peru
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.4103/ijmy.ijmy_27_20
Publisher version: https://doi.org/10.4103/ijmy.ijmy_27_20
Language: English
Additional information: © 2020 International Journal of Mycobacteriology. This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License (https://creativecommons.org/licenses/by-nc-sa/4.0/).
Keywords: Compensatory mutations, evolution, rifampicin resistance, rpoB, rpoC, tuberculosi
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10101241
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