摘要：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.
