Background : Infections of Gram-positive organisms can cause significant morbidity and mortality.  New antibacterial chemical templates are needed especially against resistant and recalcitrant infections.  A high-throughput screen was performed to identify medicinal chemistry starting points towards identifying unexplored chemical classes of antibacterials.  Methods:  A high-throughput screen identified the natural product GE2270 A and several related fermentation metabolites as active against methicillin and glycopeptide resistant S. aureus. Using co-crystal guided medicinal chemistry, semi-synthetic analogs of GE2270 A were designed, synthesized, and evaluated for in vitro potency.  The goal was to identify novel analogs that were soluble and potent (MIC <1 �g/mL) against MRSA, VRE, group A streptococcus, and C. difficile.  Potent and soluble compounds were evaluated in mouse sepsis and thigh infection models, and compared with vancomycin, linezolid, and daptomycin.  Compounds were also evaluated in the hamster C. difficile infection model, and compared with vancomycin.  Results:  Potent in vitro antibacterial activities were achieved (MIC <1 �g/mL) against MRSA, VRE, group A streptococcus, and C. difficile.  Co-crystal studies confirmed the location of binding within EF-Tu and revealed important ligand-protein interactions.  Aqueous solubility of the natural product chemical template was significantly improved and the in vivo efficacy was enhanced.  Conclusions:  A phenotypic high-throughput screen identified GE2270 A as an antibiotic drug discovery starting point.  Medicinal chemistry optimization resulted in the identification of novel and soluble antibacterials with in vitro potency and efficacy in animal models.  These studies culminated in the selection of LFF571 for further evaluation for the treatment of C. difficile infections in humans.

Discovery of LFF571 as an investigational agent for c. difficile infection

243rd National Meeting (2012)

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