Strategies against antibiotic resistance in Mycobacterium tuberculosis and ESKAPE pathogens

Purpose and goal

The spread of antimicrobial resistance among human pathogenic bacteria calls for the development of novel antibiotics. We aimed at the development of mycobacterial CysM-inhibitors and inhibitors of FabG from ESKAPE pathogens as novel antibiotic candidates. We identified CysM inhibitors that kill non-replicating M. tuberculosis with efficiency better than the available antibiotics. We have also identified FabG inhibitors targeting the enzyme in several pathogenic bacteria from the ESKAPE group.

Expected results and effects

The CysM-inhibitors developed in the course of this project are well established in their mechanism of action, mode of inhibition and their binding mode revealed by three X-ray structures of target-inhibitor complexes. The best candidates kill non-replicating M. tuberculosis effectively. The FabG inhibitors effective on several orthologs identified a binding site that may be exploited in the future as starting point.

Planned approach and implementation

The novel inhibitors were designed based on templates from previous analysis, novel compounds synthesized by the Indian partner. These were evaluated in biochemical studies and X-ray structures of target-inhibitor complexes were determined by the Swedish partner. The strongest CysM inhibitors were evaluated for antibacterial effects, cytotoxicity to present novel antibiotic candidates with established target and mechanism of action.