DISCOVERY OF LFF571 AS AN INVESTIGATIONAL AGENT FOR Clostridium difficile INFECTION

Clostridium difficile is a Gram positive, spore-forming, anaerobic bacterium which infects the lumen of the large intestine and produces toxins. This results in a range of syndromes from mild diarrhea to severe toxic megacolon and death. The prevalence and severity of C. difficile infection are increasing, causing increased morbidity and mortality. 4-Aminothiazolyl analogs of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for the treatment of serious Gram positive bacterial infections, including C. difficile infection. Optimization of the 4-aminothiazolyl-natural product template focused on improving aqueous solubility over the natural product and previous development candidates (2, 3), and improving in vitro and in vivo antibacterial activity. Structure-activity relationships, structure-solubility relationships, cocrystallographic interactions, pharmacokinetics, and efficacy in animal models of infection were characterized. These studies culminated in the identification of a dicarboxylic acid chemical series, which enhanced the solubility/efficacy profile by several orders of magnitude as compared to previous monoacid-based development candidates and led to the selection of LFF571 (4) as an investigational new drug for the treatment of C. difficile infection