Therapeutics for drug-resistant bacteria: arylmyxopyronins

Project-005 (109) PROJECT SUMMARY Myxopyronins are α-pyrone antibiotics that function by inhibiting bacterial RNA polymerase through a binding site and mechanism different from those of current antibacterial drugs. In preliminary work, we have performed mode-of-action characterization, lead validation, and lead optimization--synthesizing and evaluating more than novel 800 analogs--on myxopyronins. We have identified a novel, orally available, arylmyxopyronin lead subclass--the APY-GP subclass--that exhibits potent in vitro activity against Gram-positive bacterial pathogens (Staphylococcus spp., Streptococcus spp., and Enterococcus spp.) and fastidious Gram-negative bacterial pathogens (Haemophi/us influenzae, Moraxella catarrha/is, Legionella pneumophila, Chlamydia pneumoniae, and Mycoplasma pneumoniae)-including drug-resistant and multi-drug-resistant (MOR) strains--and that exhibits potent in vivo efficacy in a mouse MRSA lung-infection model (EDs = 12.5 mg/kg IV and 25 mg/kg PO) and in a mouse MRSA thigh-infection model (ED= 50 mg/kg PO). Our current APY-GP lead exhibits in vitro coverage and potency superior to the current intravenous-only drugs vancomycin and daptomycin and current oral drug linezolid, and exhibits in vivo efficacy comparable to linezolid. We also have identified a different novel, orally available, arylmyxopyronin lead subclass--the APY-GN subclass--that exhibits potent in vitro activity against the high-priority non-fastidious Gram-negative bacterial pathogens Acinetobacter baumannii and Burkholderia spp. Our current APY-GN_ 1 lead has in vitro coverage and potency against Acinetobacter baumannii comparable to current oral drugs delafloxacin and omadacycline and against Burkholderia spp. superior to omadacycline. We propose to perform candidate selection, candidate de-risking, and investigational new drug (IND)-enabling preclinical development for the APY-GP subclass and to perform lead optimization, candidate selection, and candidate de-risking for the APY-GN subclass. The results will provide development candidates for first-in-class, orally available, therapeutic agents effective against drug-susceptible, drug-resistant, and MOR bacterial pathogens.