The appearance ofsugImixed loci in three individuals during treatment for MDR-TB, supports the involvement ofsugIinMycobacterium tuberculosisd-cycloserine resistancein vivo

Abstract

AbstractTo study the adaptation of multi-drug resistantMycobacterium tuberculosis(MDR-TB) during treatment patients diagnosed with MDR-TB were recruited into an observational study. Clinical data andM. tuberculosisDNA at diagnosis and between seven days and two months of MDR-TB treatment were collected. The drugs prescribed were recorded. Interpretable WGS data from 118 isolates from 54 participants was obtained (11 in Belarus and 43 in Moldova) and screened for the presence of unfixed single nucleotide polymorphisms (mixed SNPs / loci).This study was performed shortly after the publication of the 2019 WHO consolidated guidelines on drug-resistant tuberculosis treatment. Existing drug supplies and procurement in one country after the switch to the all oral MDR-TB regimen in addition to patient factors, influenced the selection of and exposure to drugs.Confidently mixed SNPs were identified in samples from multiple participants in only five genes (gyrA, pncA, Rv1129c, Rv1148c, andsugI). All other genes with confidently mixed SNPs were identified in isolates from only a single individual. A significant proportion of the participants (52 of 54 participants) received d-cycloserine as part of their initial treatment, most participants who initially received d-cycloserine did not receive bedaquiline in their initial regimen (all at one site). Three different mixed SNPs were identified insugIgene from a follow up isolate from three participants (P7A, P7T, and Q6stop). Mutations insugIhave previously been reported in spontaneousin vitrod-cycloserine resistant mutants. Alterations in thesugIgene may indicate a sub optimal d-cycloserine containing regimen and potentially be of clinical significance with respect to adaptation to d-cycloserine. Monitoring the accumulation of low frequency escape mutants may help identify regimens insufficiently powerful to block the accumulation of antimicrobial resistance mutants and identify drug(s) at risk of resistance selection.