@article {680650, title = {The role of epistasis in amikacin, kanamycin, bedaquiline, and clofazimine resistance in Mycobacterium tuberculosis complex}, journal = {Antimicrobial Agents and Chemotherapy}, year = {2021}, abstract = { Abstract Antibiotic resistance among bacterial pathogens poses a major global health threat.\ M. tuberculosis\ complex (MTBC) is estimated to have the highest resistance rates of any pathogen globally. Given the slow growth rate and the need for a biosafety level 3 laboratory, the only realistic avenue to scale up drug susceptibility testing (DST) for this pathogen is to rely on genotypic techniques. This raises the fundamental question of whether a mutation is a reliable surrogate for phenotypic resistance or whether the presence of a second mutation can completely counteract its effect, resulting in major diagnostic errors (i.e. systematic false resistance results). To date, such epistatic interactions have only been reported for streptomycin that is now rarely used. By analyzing more than 31,000 MTBC genomes, we demonstrated that the\ eis\ C-14T promoter mutation, which is interrogated by several genotypic DST assays endorsed by the World Health Organization, cannot confer resistance to amikacin and kanamycin if it coincides with loss-of-function (LoF) mutations in the coding region of\ eis. To our knowledge, this represents the first definitive example of antibiotic reversion in MTBC. Moreover, we raise the possibility that\ mmpR\ (Rv0678) mutations are not valid markers of resistance to bedaquiline and clofazimine if these coincide with a LoF mutation in the efflux pump encoded by\ mmpS5\ (Rv0677c) and\ mmpL5\ (Rv0676c). }, url = {https://journals.asm.org/doi/10.1128/AAC.01164-21}, author = {Vargas R and Freschi L and Spitaleri A, and Tahseen S and Barilar I and Neimann S, and Miotto P and Cirillo D and Koser C, and MR, Farhat} }