Discovery through chemical synthesis of antibiotics effective against modern bacterial pathogens

PROJECT SUMMARY/ABSTRACT In recent decades, the emergence of antibiotic resistance in bacteria has greatly outpaced the discovery of novel antibacterial agents. This research is focused on the synthesis and biological study of antibiotics effective against these modern pathogens of urgent threat. To this end, the lincosamides have been identified as an underexploited class of antibiotics. No new lincosamide has entered the market since clindamycin was approved more than 50 years ago (FDA, 1970). Growing resistance to clindamycin and its propensity to induce life- threatening Clostridioides difficile (C. difficile) colitis have limited its utility in today's armamentarium. Due to the structural complexity of this class of natural products, semi-synthetic strategies are insufficient to support future antibiotic drug discovery within this or related scaffolds. Here, efficient synthetic pathways will be developed and implemented to prepare a large collection of lincosamide analogs inaccessible by any other means. These include analogs of a lead candidate, iboxamycin, which features a novel bicyclic oxepanoprolinamide scaffold and is efficacious in vitro and in vivo against a broad range of multi-drug resistant (MDR) bacteria. The latter include MDR ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.), identified by the WHO as targets of highest priority in antibiotic development. By elucidating the mechanistic underpinnings and drivers of in vivo efficacy of iboxamycin and future lead antibiotics, this research will deliver multiple novel antibiotic scaffolds for preclinical exploration to target these challenging pathogens.