Structure-Activity Relationship of Anti-<i>Mycobacterium abscessus</i> Piperidine-4-carboxamides, a New Class of NBTI DNA Gyrase Inhibitors.
Beuchel A, Robaa D, Negatu DA, Madani A, Alvarez N, Zimmerman MD, Richter A, Mann L, Hoenke S, Csuk R, Dick T, Imming P.
<i>Mycobacterium abscessus</i> causes difficult-to-cure pulmonary infections. The bacterium is resistant to most anti-infective agents, including first line antituberculosis (anti-TB) drugs. MMV688844 (<b>844</b>) is a piperidine-4-carboxamide (P4C) with bactericidal properties against <i>M. abscessus</i>. We recently identified DNA gyrase as the molecular target of <b>844</b>. Here, we present <i>in silico</i> 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 <b>844</b> leading to analogues showing increased antibacterial activity. Selected derivatives were tested for their inhibitory activity against recombinant <i>M. abscessus</i> DNA gyrase. Further optimization of the lead structures led to improved stability in mouse plasma and increased oral bioavailability.