Abstract
ABSTRACTNew, more-effective drugs for the treatment of lung disease caused by nontuberculous mycobacteria (NTM) are needed. Among NTM opportunistic pathogens, Mycobacterium abscessus is the most difficult to cure and intrinsically multidrug resistant. In a whole-cell screen of a compound collection active against Mycobacterium tuberculosis, we previously identified the piperidine-4-carboxamide (P4C) MMV688844 (844) as a hit against M. abscessus. Here, we identified a more potent analog of 844 and showed that both the parent and improved analog retain activity against strains representing all three subspecies of the M. abscessus complex. Furthermore, P4Cs showed bactericidal and antibiofilm activity. Spontaneous resistance against the P4Cs emerged at a frequency of 10−8/CFU and mapped to gyrA and gyrB encoding the subunits of DNA gyrase. Biochemical studies with recombinant M. abscessus DNA gyrase showed that P4Cs inhibit the wild-type enzyme but not the P4C-resistant mutant. P4C-resistant strains showed limited cross-resistance to the fluoroquinolone moxifloxacin, which is in clinical use for the treatment of macrolide-resistant M. abscessus disease, and no cross-resistance to the benzimidazole SPR719, a novel DNA gyrase inhibitor in clinical development for the treatment of mycobacterial diseases. Analyses of P4Cs in recA promoter-based DNA damage reporter strains showed induction of recA promoter activity in the wild type but not in the P4C-resistant mutant background. This indicates that P4Cs, similar to fluoroquinolones, cause DNA gyrase-mediated DNA damage. Together, our results show that P4Cs present a novel class of mycobacterial DNA gyrase inhibitors with attractive antimicrobial activities against the M. abscessus complex.
Highlights
New, more-effective drugs for the treatment of lung disease caused by nontuberculous mycobacteria (NTM) are needed
We and others have shown that focused libraries of compounds active against M. tuberculosis provide an attractive source of hits active against NTM [17,18,19,20,21]
We show that 844 and a more potent analog are broadly active against a collection of strains representing the three subspecies of the M. abscessus complex
Summary
More-effective drugs for the treatment of lung disease caused by nontuberculous mycobacteria (NTM) are needed. Analyses of P4Cs in recA promoter-based DNA damage reporter strains showed induction of recA promoter activity in the wild type but not in the P4C-resistant mutant background. This indicates that P4Cs, similar to fluoroquinolones, cause DNA gyrase-mediated DNA damage. We and others have shown that focused libraries of compounds active against M. tuberculosis provide an attractive source of hits active against NTM [17,18,19,20,21] In one such screen, using the Pathogen Box collection from Medicines for Malaria Venture (https://www.mmv.org/mmv-open/pathogen-box), we identified the piperidine-4-carboxamide (P4C) MMV688844 [844] as a hit active against our M. abscessus screening strain M. abscessus subsp. This work identified a novel mycobacterial DNA gyrase inhibitor
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