TY - JOUR
T1 - Genetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid
AU - Gómez-González, Paula J.
AU - Perdigao, Joao
AU - Gomes, Pedro
AU - Puyen, Zully M.
AU - Santos-Lazaro, David
AU - Napier, Gary
AU - Hibberd, Martin L.
AU - Viveiros, Miguel
AU - Portugal, Isabel
AU - Campino, Susana
AU - Phelan, Jody E.
AU - Clark, Taane G.
N1 - Funding Information:
PJG-G is funded by an MRC-LID PhD studentship. JEP is funded by a Newton Institutional Links Grant (British Council, no. 261868591). TGC is funded by the Medical Research Council UK (Grant no. MR/M01360X/1, MR/ N010469/1, MR/R025576/1, and MR/R020973/1) and BBSRC (Grant no. BB/R013063/1). SC is funded by Medical Research Council UK grants (ref. MR/M01360X/1, MR/R025576/1, and MR/R020973/1). JP is supported by the Portuguese FCT (ref. CEECIND/00394/2017). PG is the recipient of a PhD studentship from the Portuguese FCT (ref. 2020.05942.BD). The authors declare no conflicts of interest.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/9/30
Y1 - 2021/9/30
N2 - 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.
AB - 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.
KW - Bacterial genes
KW - Genetics
KW - Microbial genetics
UR - http://www.scopus.com/inward/record.url?scp=85116334642&partnerID=8YFLogxK
U2 - 10.1038/s41598-021-98862-4
DO - 10.1038/s41598-021-98862-4
M3 - Article
C2 - 34593898
AN - SCOPUS:85116334642
SN - 2045-2322
VL - 11
SP - 1
EP - 13
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 19431
ER -
