2. Academic Validation
  3. Structure-Activity Relationship of Anti- Mycobacterium abscessus Piperidine-4-carboxamides, a New Class of NBTI DNA Gyrase Inhibitors

Structure-Activity Relationship of Anti- Mycobacterium abscessus Piperidine-4-carboxamides, a New Class of NBTI DNA Gyrase Inhibitors

  • ACS Med Chem Lett. 2022 Feb 28;13(3):417-427. doi: 10.1021/acsmedchemlett.1c00549.
Andreas Beuchel 1,  Dina Robaa 1,  Dereje A Negatu 2 3,  Abdeldjalil Madani 2,  Nadine Alvarez 2,  Matthew D Zimmerman 2,  Adrian Richter 1,  Lea Mann 1,  Sophie Hoenke 4,  René Csuk 4,  Thomas Dick 2 5 6,  Peter Imming 1
Affiliations

Affiliations

  • 1 Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany, Kurt-Mothes-Str. 3, 06120 Halle (Saale), Germany.
  • 2 Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey 07110, United States.
  • 3 Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), Addis Ababa University, Addis Ababa 1000, Ethiopia.
  • 4 Institut für Chemie, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, 06120 Halle (Saale), Germany.
  • 5 Department of Medical Sciences, Hackensack Meridian School of Medicine, Nutley, New Jersey 07110, United States.
  • 6 Department of Microbiology and Immunology, Georgetown University, Washington, D.C. 20057, United States.
PMID: 35300094 DOI: 10.1021/acsmedchemlett.1c00549
Abstract

Mycobacterium abscessus causes difficult-to-cure pulmonary infections. The bacterium is resistant to most anti-infective agents, including first line antituberculosis (anti-TB) drugs. MMV688844 (844) is a piperidine-4-carboxamide (P4C) with bactericidal properties against M. abscessus. We recently identified DNA gyrase as the molecular target of 844. Here, we present in silico docking and genetic evidence suggesting that P4Cs display a similar binding mode to DNA gyrase as gepotidacin. Gepotidacin is a member of the Novel Bacterial Topoisomerase Inhibitors (NBTIs), a new class of nonfluoroquinolone DNA gyrase poisons. Thus, our work suggests that P4Cs present a novel structural subclass of NBTI. We describe structure-activity relationship studies of 844 leading to analogues showing increased Antibacterial activity. Selected derivatives were tested for their inhibitory activity against recombinant M. abscessus DNA gyrase. Further optimization of the lead structures led to improved stability in mouse plasma and increased oral bioavailability.

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