Friday, May 9, 2025
5/9/2025
Beta-Lactamase Inhibitors Sensitize Multidrug-Resistant Gram-negative Pathogens to Innate Immune Clearance - Project Summary The goal of the proposed five-year training program is to support the development of the applicant's independent research career as an academic pediatric infectious diseases doctor focused on host-directed therapeutics for multidrug-resistant pathogens. The applicant completed medical school at Stanford University School of Medicine, pediatrics residency training at Boston Children's Hospital/Harvard Medical School and is currently completing her fellowship training in pediatric infectious diseases at the Children's Hospital of Philadelphia (CHOP), with the plan to transition to faculty at the University of California San Diego (UCSD) in 2020. The candidate's goals are to develop and refine the essential skills that will be required for a successful career as an independent investigator. The candidate specifically seeks to gain expertise in murine models of infection, bacterial genetics, genomics and advanced fluorescence microscopy to augment her research skills in immunology. Her long-term goal is to investigate and develop immune based treatment and therapeutic strategies to improve treatment paradigms and clinical outcomes for patients with highly drug-resistant infections. The mentor for this award is Professor Victor Nizet, an eminent physician-scientist and established leader in junior faculty development, innate immunology and experimental therapeutics. To add depth and breadth to the scientific and career guidance of the applicant, a Mentoring Committee is composed of scientists and physician- scientists from diverse and complementary fields. Dr. Ulloa will also benefit from the unparalleled resources and the unique, interdisciplinary working groups at UCSD including the Center for Immunity, Infection & Inflammation; the Center for Drug Discovery and Innovation; and the Collaborative to Halt Antibiotic-Resistant Microbes. The applicant's proposal is relevant to the U.S. National Action Plan to combat the increasing prevalence of drug-resistant pathogens that threaten our ability to manage life-threatening bacterial infections, and that pose significant challenges in balancing the efficacy and toxicity of potential antibiotic therapies. A solution proposed herein is to repurpose drugs that increase the antibacterial efficiency of important innate immune components. The foundation for this proposal is based on the candidate's first-author manuscript that describes how multidrug- resistant bacteria are sensitized to killing by the innate immune system in the presence of β-lactamase inhibitors, despite prevailing logic predicting this monotherapy to be fruitless. The mechanisms for such synergy and its therapeutic potential in vivo remain to be elucidated. The aims of this proposal are 1) to identify the mechanistic basis for β-lactamase inhibitor and antimicrobial peptide synergy, and 2) to investigate the therapeutic impact of β-lactamase inhibitors in vivo. These studies will provide a rationale for repurposing certain FDA-approved drugs, with known safety and tolerability, as adjunctive immunotherapies for the treatment of drug-resistant infections.
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