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Genetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid
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Genetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid
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Journal Article
Genetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid
2021
Overview
Tuberculosis (TB), caused by
Mycobacterium tuberculosis
, is one of the deadliest infectious diseases worldwide. Multidrug and extensively drug-resistant strains are making disease control difficult, and exhausting treatment options. New anti-TB drugs bedaquiline (BDQ), delamanid (DLM) and pretomanid (PTM) have been approved for the treatment of multi-drug resistant TB, but there is increasing resistance to them. Nine genetic loci strongly linked to resistance have been identified (
mmpR5
,
atpE
, and
pepQ
for BDQ;
ddn
,
fgd1
,
fbiA
,
fbiB
,
fbiC
, and
fbiD
for DLM/PTM). Here we investigated the genetic diversity of these loci across >33,000
M
. tuberculosis
isolates. In addition, epistatic mutations in
mmpL5-mmpS5
as well as variants in
ndh
, implicated for DLM/PTM resistance in
M. smegmatis
, were explored
.
Our analysis revealed 1,227 variants across the nine genes, with the majority (78%) present in isolates collected prior to the roll-out of BDQ and DLM/PTM. We identified phylogenetically-related mutations, which are unlikely to be resistance associated, but also high-impact variants such as frameshifts (e.g. in
mmpR5
,
ddn
) with likely functional effects, as well as non-synonymous mutations predominantly in MDR-/XDR-TB strains with predicted protein destabilising effects. Overall, our work provides a comprehensive mutational catalogue for BDQ and DLM/PTM associated genes, which will assist with establishing associations with phenotypic resistance; thereby, improving the understanding of the causative mechanisms of resistance for these drugs, leading to better treatment outcomes.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ Antitubercular Agents - pharmacology
/ Diarylquinolines - pharmacology
/ Drug Resistance, Multiple, Bacterial - genetics
/ Humanities and Social Sciences
/ Humans
/ Mutation
/ Mycobacterium smegmatis - genetics
/ Mycobacterium tuberculosis - drug effects
/ Mycobacterium tuberculosis - genetics
/ Nitroimidazoles - pharmacology
/ Science
