Development of Novel S. aureus Antibiotics with Reduced Resistance Susceptibility

DESCRIPTION provided by applicant Widespread antibiotic use has accelerated S aureus resistance to almost all marketed antibiotic classes including beta lactams fluoroquinolones macrolides aminoglycosides tetracyclines as well as the newer linezolid and daptomycin Methicillin resistant S aureus MRSA is an increasing public health threat with deaths from MRSA infections already comparable to HIV AIDS in and increasing since then Thus there is a clear imperative for developing new therapeutic agents In recent work we have developed antimicrobial compounds that show low micromolar antibacterial activity against both wild type and methicillin resistant S aureus through dual mechanism activity initially inducing rapid depolarization of bacterial membranes followed by cell penetration and target based bacterial killing through inhibition of the enzyme enoyl reductase or FabI Our inhibitors show mid to low nanomolar inhibition of FabI with promising metabolic stability and cytotoxicity for our initial compounds Based on extensive preliminary studies including crystal structures of multiple inhibitors co crystallized with FabI mechanistic characterization of a unique mode of inhibition and characterization of inhibitor metabolic stabilities we now propose to develop improved antimicrobial agents through an iterative process of determining detailed structure based molecular design synthetic medicinal chemistry initial preclinical toxicology and pharmacokinetic characterization with specific proposed milestones and go no go criteria The goal of this Phase I STTR application is to develop proof of concept for antibacterial lead compounds against drug resistant S aureus that are safe and efficacious PUBLIC HEALTH RELEVANCE Widespread antibiotic use has accelerated drug resistance in the bacterium Staphylococcus aureus to almost all marketed antibiotic classes including beta lactams fluoroquinolones macrolides aminoglycosides tetracyclines as well as the newer linezolid and daptomycin Methicillin resistant S aureus MRSA is an increasing public health threat with deaths from MRSA infections already comparable to HIV AIDS in and increasing since then Our research will utilize a combination of computational chemistry enzymology X ray crystallography synthetic medicinal mutational resistance analysis and preclinical biological studies to develop inhibitors of an enzyme in the fatty acid biosynthetic pathway that is called enoyl reductase or FabI We are developing these as new potential drugs for the treatment of S aureus and its drug resistant strain MRSA