Efflux pump gene single nucleotide variants associated with resistance in Mycobacterium tuberculosis isolates with discrepant drug genotypes

Document Type

Article

Department

Pathology and Laboratory Medicine; Paediatrics and Child Health

Abstract

Introduction: Single nucleotide variants (SNVs) in Mycobacterium tuberculosis (MTB) genomes can predict multi-drug resistance (MDR) but not all phenotype - genotype correlations can be explained. We investigated SNVs in efflux pumps (EP) in the context of MTB drug resistance.
Methods: We analysed 2221 MTB genomes from 1432 susceptible and 200 MDR, 172 pre-XDR (extensively drug resistant) and 417 XDR isolates. Analysis of 47 EP genes was conducted using MTB-VCF, an in-house bioinformatics pipeline. SNVs were categorized according to their SIFT/Polyphen scores. Resistance genotypes were also called using the TB-Profiler tool.
Results: Genome comparisons between susceptible and DR isolates identified 418 unique SNVs in EP of which; 53.5% were in MDR, 68.9% in pre-XDR and 61.3% in XDR isolates. Twenty EP had unique SNVs with a high SIFT/PolyPhen score, comprising 38 unique SNVs. Sixteen SNVs across 12 EP genes were significantly associated with drug resistance and enriched in preXDR and XDR strains. These were 12 previously reported SNVs (in Rv0191, Rv0507, Rv0676, Rv1217, Rv1218, Rv1273, Rv1458, Rv1819 and Rv2688) and four novel SNVs (in Rv1877 and Rv2333). We investigated the 16 SNVs in 52 MDR isolates with phenotype-genotype discrepancy to rifampicin (RIF), isoniazid (INH) and flouroquinolones. SNVs associated with RIF and INH (Rv1217_1218, Rv1819, Rv0450, Rv1458, Rv3827, Rv0507, Rv0676, Rv1273 and Rv2333), and with fluoroquinolone (Rv2688) resistance were present in these discrepant strains.
Conclusions: Considering SNVs in efflux pumps as part of MTB genome-based resistance interpretation may add value especially in evaluation of XDR resistance in strains with phenotype-genotype discrepancies.

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Volume, issue and pagination are not provided by the author/publisher.

Publication (Name of Journal)

Journal of Global Antimicrobial Resistance

DOI

10.1016/j.jgar.2024.05.006

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