1. Academic Validation
  2. Piperidine-4-Carboxamides Target DNA Gyrase in Mycobacterium abscessus

Piperidine-4-Carboxamides Target DNA Gyrase in Mycobacterium abscessus

  • Antimicrob Agents Chemother. 2021 Jul 16;65(8):e0067621. doi: 10.1128/AAC.00676-21.
Dereje Abate Negatu  # 1 2 Andreas Beuchel  # 3 Abdeldjalil Madani  # 1 Nadine Alvarez 1 Chao Chen 1 Wassihun Wedajo Aragaw 1 Matthew D Zimmerman 1 Benoît Laleu 4 Martin Gengenbacher 1 5 Véronique Dartois 1 5 Peter Imming 3 Thomas Dick 1 5 6
Affiliations

Affiliations

  • 1 Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, USA.
  • 2 Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), Addis Ababa University, Addis Ababa, Ethiopia.
  • 3 Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany.
  • 4 Medicines for Malaria Venture, Geneva, Switzerland.
  • 5 Department of Medical Sciences, Hackensack Meridian School of Medicine, Nutley, New Jersey, USA.
  • 6 Department of Microbiology and Immunology, Georgetown University, Washington, DC, USA.
  • # Contributed equally.
Abstract

New, 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.

Keywords

DNA gyrase; MMV688844; Mycobacterium abscessus; NTM; nontuberculous mycobacteria.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12930
    99.50%, Gyrase B Inhibitor