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Multidrug-resistant (MDR) strains of bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) are becoming more prominent in BC’s hospitals and community settings. Alarmingly, while antibiotic resistance is on the rise, antimicrobial discovery research is on the decline, and only a few new drugs to fight these bacteria have emerged in the last few years.

To fulfill the need for discovery and development of new classes of antibiotics to combat these bacterial pathogens, this project aimed at developing potential new antibiotics for the treatment of MRSA. The team focused on optimizing lead pyruvate kinase (PK) compound series to enable in vivo proof-of-concept of the therapeutic potential of inhibiting bacterial PK in a mouse model of MRSA infection.

It was found that the potency of lead compound was highly attenuated in the presence of plasma proteins, effectively raising the in vivo MIC many fold and beyond the achievable concentration after oral dosing at acceptable doses.

Although a hydrazone class of PK inhibitors with suitably attenuated plasma protein binding was unable to be identified through this research effort, some compounds in the other classes were less attenuated in the plasma and thus identified as excellent leads for further optimization. This project also established a robust thigh infection model as a screening tool for measuring compound efficacy and optimized nanoparticle formulation of the compounds for efficient delivery in a mouse model of infection.