Pharmacology Core

SUMMARY The global escalation of antimicrobial resistance (AMR) poses a significant threat to public health, underscoring the imperative for the development of novel antibiotics targeting high-risk AMR pathogens. Nevertheless, prevailing approaches to drug development often minimize considerations of tissue exposure/selectivity, resulting in elevated rates of candidate attrition. The CETR Pharmacology Core is dedicated to mitigating attrition stemming from pharmacokinetic (PK) and toxicity-related factors by providing a rigorous selection process for pharmacologic profiling of drug candidates. The Core will provide comprehensive support for all CETR Projects directed at combatting clinically significant, high-risk, drug-resistant bacterial pathogens, including non- tuberculous mycobacteria (NTMs), methicillin-resistant Staphylococcus aureus, Enterococci, Neisseria gonorrhoea, Acinetobacter baumannii, and Burkholderia spp. All five Projects have compounds in the advanced lead optimization phase, and the Core's principal objective is to expedite the progression of these compounds for preclinical drug candidate (PDC) selection and support Investigational New Drug (IND)-enabling studies. The Core employs a modern Pharma-based approach with customized strategies for timely compound assessment throughout development phases. Our approach involves tailored in vitro and in vivo quantitative evaluations of the PK-PD and safety of candidate compounds at multiple levels to assess whether they meet threshold metrics for progression. The Core functions as an integrated component of the overall drug development enterprise, which includes close interactions with the Animal Model and Medicinal Chemistry Cores. We will conduct detailed toxicology studies to evaluate the safety profile of candidate compounds, identifying any potential adverse effects. In addition to supporting the progression of compounds through PDC selection, the Core will also assume a crucial role in supporting early Good Laboratory Practice (GLP) and toxicology studies. We will maintain close collaboration with regulatory experts to ensure adherence to federal requirements and guidelines in all studies. Early milestones include advanced lead optimization and the nomination of PDCs that meet specific Target Product Profile criteria, which requires striking the right balance between candidate potency, exposure, and therapeutic index. Milestones for IND enabling studies prioritize toxicology-based de-risking of compounds and addressing drug target attainment for human dose projections, which will be accomplished through close interactions with expert consultants in pharmacodynamic modeling and toxicology. The overall Core operation benefits from a well-established infrastructure supporting CETR based drug discovery programs involving academic and industry partners. Overall, the Pharmacology Core provides comprehensive support to expedite the development of safe and efficacious therapeutics addressing drug-resistant bacterial infections.