Resistance to Thiacetazone Derivatives Active against Mycobacterium abscessus Involves Mutations in the MmpL5 Transcriptional Repressor MAB_4384

Abstract

Available chemotherapeutic options are very limited against Mycobacterium abscessus, which imparts a particular challenge in the treatment of cystic fibrosis (CF) patients infected with this rapidly growing mycobacterium. New drugs are urgently needed against this emerging pathogen, but the discovery of active chemotypes has not been performed intensively. Interestingly, however, the repurposing of thiacetazone (TAC), a drug once used to treat tuberculosis, has increased following the deciphering of its mechanism of action and the detection of significantly more potent analogues. We therefore report studies performed on a library of 38 TAC-related derivatives previously evaluated for their antitubercular activity. Several compounds, including D6, D15, and D17, were found to exhibit potent activity in vitro against M. abscessus, Mycobacterium massiliense, and Mycobacterium bolletii clinical isolates from CF and non-CF patients. Similar to TAC in Mycobacterium tuberculosis, the three analogues act as prodrugs in M. abscessus, requiring bioactivation by the EthA enzyme, MAB_0985. Importantly, mutations in the transcriptional TetR repressor MAB_4384, with concomitant upregulation of the divergently oriented adjacent genes encoding an MmpS5/MmpL5 efflux pump system, accounted for high cross-resistance levels among all three compounds. Overall, this study uncovered a new mechanism of drug resistance in M. abscessus and demonstrated that simple structural optimization of the TAC scaffold can lead to the development of new drug candidates against M. abscessus infections.

Bedaquiline Inhibits the ATP Synthase in Mycobacterium abscessus and Is Effective in Infected Zebrafish

“…In addition, inhibitors of energy metabolism may prove highly suitable in drug combination regimens due to interference with drug efflux (53). Efflux pumps have emerged recently as important determinants in drug resistance mechanisms in M. tuberculosis (41,42), as well as in M. abscessus (7). Because a sufficiently high proton motive force and ATP levels have to be maintained for drug extrusion mechanisms, draining the energy supply of efflux pumps may represent an alternative strategy to impede drug efflux.…”

“…This confirmed that TB drug discovery platforms could easily be exploited to screen for M. abscessus-active compounds. This led, for instance, to the identification of a piperidinol-based compound (6) or thiacetazone (TAC) derivatives (7), which exhibit potent activity against M. abscessus. However, the quest for discovering potent novel active drugs against M. abscessus could also rely on repurposing TB drugs.…”

The diverse family of MmpL transporters in mycobacteria: from regulation to antimicrobial developments

“…C). These mutations in TetR resulted in high induction levels of the mmpS5 and mmpL5 transcripts (Halloum et al ., ). Compellingly, over‐expression of mmpS5/mmpL5 in these resistant mutants did not result in cross‐resistance to any other antibiotics utilised to treat M. abscessus infections, highlighting the specificity toward the compound exported.…”

Nontuberculous mycobacterial lung disease: ecology, microbiology, pathogenesis, and antibiotic resistance mechanisms

“…Mutations of the mmpS5/mmpL5 operon were associated with resistance to bedaquiline and clofazimine in M. intracellulare and to thiacetazone in M. abscessus [159,160]. Further research may also reveal roles for other efflux pumps of NTM, such as the mmpL gene, in antibiotic resistance.…”

“…MmpLs belongs to the resistance-nodulation-cell division permease superfamily [157]. Since Pasca and colleague [158] first reported that the mmpL7 gene from M. tuberculosis conferred resistance to isoniazid when overexpressed in M. smegmatis, orthologs of mmpL and mmpS genes have been characterized and identified in NTM [159].…”