Role of Epistasis in Amikacin, Kanamycin, Bedaquiline, and Clofazimine Resistance in Mycobacterium tuberculosis Complex

• Published in: Antimicrobial agents and chemotherapy 2021-10, Vol.65 (11), p.e0116421
• Main Authors: Vargas, Jr, Roger, Freschi, Luca, Spitaleri, Andrea, Tahseen, Sabira, Barilar, Ivan, Niemann, Stefan, Miotto, Paolo, Cirillo, Daniela Maria, Köser, Claudio U, Farhat, Maha R
• Format: Article
• Language: English
• Subjects: Amikacin - pharmacology; Antitubercular Agents - pharmacology; Antitubercular Agents - therapeutic use; Clofazimine - pharmacology; Diarylquinolines; Drug Resistance, Multiple, Bacterial - genetics; Editor's Pick; Epistasis, Genetic; Genomics and Proteomics; Humans; Kanamycin - pharmacology; Mechanisms of Resistance; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis - genetics; Tuberculosis, Multidrug-Resistant - drug therapy; Tuberculosis, Multidrug-Resistant - genetics
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.01164-21

Antibiotic resistance among bacterial pathogens poses a major global health threat. Mycobacterium tuberculosis complex (MTBC) is estimated to have the highest resistance rates of any pathogen globally. Given the low 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 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 . To our knowledge, this represents the first definitive example of antibiotic reversion in MTBC. Moreover, we raise the possibility that ( ) mutations are not valid markers of resistance to bedaquiline and clofazimine if these coincide with an LoF mutation in the efflux pump encoded by ( ) and ( ).