Systematic review of mutations associated with resistance to the new and repurposedMycobacterium tuberculosisdrugs bedaquiline, clofazimine, linezolid, delamanid and pretomanid

Abstract

Background Improved genetic understanding of Mycobacterium tuberculosis (MTB) resistance to novel and repurposed anti-tubercular agents can aid the development of rapid molecular diagnostics. Methods Adhering to PRISMA guidelines, in March 2018, we performed a systematic review of studies implicating mutations in resistance through sequencing and phenotyping before and/or after spontaneous resistance evolution, as well as allelic exchange experiments. We focused on the novel drugs bedaquiline, delamanid, pretomanid and the repurposed drugs clofazimine and linezolid. A database of 1373 diverse control MTB whole genomes, isolated from patients not exposed to these drugs, was used to further assess genotype–phenotype associations. Results Of 2112 papers, 54 met the inclusion criteria. These studies characterized 277 mutations in the genes atpE, mmpR, pepQ, Rv1979c, fgd1, fbiABC and ddn and their association with resistance to one or more of the five drugs. The most frequent mutations for bedaquiline, clofazimine, linezolid, delamanid and pretomanid resistance were atpE A63P, mmpR frameshifts at nucleotides 192–198, rplC C154R, ddn W88* and ddn S11*, respectively. Frameshifts in the mmpR homopolymer region nucleotides 192–198 were identified in 52/1373 (4%) of the control isolates without prior exposure to bedaquiline or clofazimine. Of isolates resistant to one or more of the five drugs, 59/519 (11%) lacked a mutation explaining phenotypic resistance. Conclusions This systematic review supports the use of molecular methods for linezolid resistance detection. Resistance mechanisms involving non-essential genes show a diversity of mutations that will challenge molecular diagnosis of bedaquiline and nitroimidazole resistance. Combined phenotypic and genotypic surveillance is needed for these drugs in the short term.

Mutations in fbiD ( Rv2983 ) as a Novel Determinant of Resistance to Pretomanid and Delamanid in Mycobacterium tuberculosis

“…Second, with one exception, Rv2983 and fbiB mutants showed only low-level resistance to delamanid despite high-level resistance to pretomanid. This finding adds to a previous report associating fbiB mutations with low-level delamanid resistance (24) and, together with differences in how delamanid resistance has been defined, may explain why neither fbiB nor Rv2983 mutants have yet been associated with delamanid resistance in clinical isolates (29,35). Third, we provide additional evidence that Rv2983 is required for F 420 biosynthesis in M. tuberculosis in support of its recently elucidated role as the guanlylyltransferase fbiD (20).…”

Mutations infbiD (Rv2983)as a novel determinant of resistance to pretomanid and delamanid inMycobacterium tuberculosis

“…Second, with one exception, Rv2983 and fbiB mutants showed only low-level resistance to delamanid despite high-level resistance to pretomanid. This finding adds to a previous report associating fbiB mutations with low-level delamanid resistance (24) and, together with differences in how delamanid resistance has been defined, may explain why neither fbiB nor Rv2983 mutants have yet been associated with delamanid resistance in clinical isolates (29,35). Third, we provide additional evidence that Rv2983 is required for ranged from 1 in 10 5 to 7 in 10 7 CFU (22)(23)(24)(36)(37)(38), which is consistent with our findings in the lungs of untreated BALB/c mice.…”

Deciphering Bedaquiline and Clofazimine Resistance in Tuberculosis: An Evolutionary Medicine Approach

“…However, the four mutations which were most frequently observed were: 192 ins g (64fs), A99V, 193 del g (65fs), and R50W; these mutations were detected in 19, 17, 13, and 12 single selected clones, respectively (Table 1). Notably, nucleotides 192-198 were also identified as a hotspot for frameshifting variation in a prior review, potentially due to the homopolymeric nature of this region 41 . As mentioned before, no mutant clone had more than one resistance mediating variant in Rv0678 or atpE, however, 38 mutants harbored a second mutation in one of 14 genes that have not been previously proposed to be associated with resistance against BDQ and/or CFZ (Table S3).…”