Preclinical assessment of phosphopyricin and analogs as novel phosphine-based antibiotics

The threat of antimicrobial resistance is exemplified by the multidrug-resistant (MDR) ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). These bacteria cause infections that are difficult and costly to treat, contributing to 700,000 global deaths annually. Despite their status as priority pathogens, there are few antibiotics in preclinical and clinical development that are effective against ESKAPE pathogens. This critical need may be met by non-phosphate organophosphorus compounds such as phosphopyricin, which exhibits antibiotic activity against methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecium (VRE). My proposed research will provide a comprehensive preclinical assessment of phosphopyricin and its analogs as the first agents in a novel class of phosphine-based antibiotics. Anticipated experiments correspond to one of three objectives: physicochemical and pharmacokinetic characterization, in vitro toxicity evaluation, and in vivo toxicity and efficacy evaluations. Physicochemical properties relevant to antibiotic design will be predicted and experimentally determined for each compound, while plasma protein binding and intestinal permeability will be assessed in vitro. Toxicity assays in human-derived cell lines will determine if any compounds are inherently toxic to the intestine and liver. Finally, two acute in vivo assays in mice will establish a maximum tolerable dose of phosphopyricin and evaluate its antibiotic efficacy in a MDRS. aureus-inoculated wound model. This project will offer significant contributions to antibiotic research, the fields of pharmacology and toxicology, and the global fight against ESKAPE pathogens.