Antivirulence Inhibitors of Bacterial Type IV Pili: A Strategy Against Antibiotic Resistance

About This Grant

Project Summary Antibiotic resistance (ABR) poses an urgent and escalating threat to global public health. This crisis is fueled by the widespread use, overuse, and misuse of antibiotics in both clinical and agricultural settings. By targeting essential bacterial processes, antibiotics exert strong selective pressure that drives the survival and expansion of resistant populations. This evolutionary pressure, compounded by the inherent genetic adaptability of bacteria and horizontal gene transfer, accelerates the emergence and spread of ABR. An emerging but underutilized strategy to combat ABR is antivirulence therapy, which targets virulence factors required for pathogenesis but not for bacterial viability. Because these agents do not threaten bacterial survival directly, they impose less selective pressure for resistance development. Immunotherapeutics that neutralize bacterial toxins provide the proof of principle for this approach. A promising and scalable direction within antivirulence therapy lies in the development of small-molecule inhibitors that interfere with virulence mechanisms. One of the most compelling yet understudied targets is the type IV pilus (T4P), which is present in several high-priority Gram-negative pathogens. It is a bacterial cell surface structure composed of multiple conserved proteins serving as attractive and druggable targets. The overarching goal of this project is to advance T4P-targeting antivirulence therapeutics through two specific aims. Aim 1 will conduct structure–activity relationship (SAR) studies of a novel T4P inhibitor to improve potency and selectivity. Aim 2 will perform high- throughput screening using an innovative phenotypic platform to identify new chemical entities that inhibit T4P biogenesis and function. Successful completion of these aims will establish a robust pipeline for the discovery and preclinical development of T4P-targeting antivirulence agents, laying the foundation for a novel class of therapeutics to combat antibiotic-resistant infections.