Please join the Department of Chemistry and Biochemistry on Wednesday, December 4 at 1pm in CL 1009 for a thesis defense by Samuel T. Moore, Master of Science in Chemical Sciences (MSCB) candidate.
 

Title: Design, Synthesis, and NMR-Guided Characterization of a Targeted Covalent Inhibitor-Like Molecule Against Ivyp1 from P. aeruginosa

Abstract: Multi-drug resistance poses a serious threat to future generations and historical antibiotic pipelines; consequently, the medical and economic burdens associated with treating multidrug-resistant bacteria are substantiated. In this context, P. aeruginosa (PA) emerges as one of the most significant healthcare challenges, being a leading cause of resistance-associated mortality worldwide. Despite modern efforts to combat these poor outcomes, drug-resistant cases continue to rise, and the need for novel antibiotic treatment is apparent. To this end, we investigated relevant resistance mechanisms and past antibiotic targets within PA, and in doing so, we identified relationships between peptidoglycan biology and a periplasmic protein, Inhibitor of Vertebrate Lysozyme (Ivyp1). Following this connection and previous reports, we formulated a drug discovery campaign to satisfy the need for novel antibiotics in PA. Our hypothesis poses that drug-based inhibition of Ivyp1 will perturb peptidoglycan biology in P. aeruginosa, rendering PA susceptible to combinatorial antibiotic treatments. Here, we report the rational design and synthesis of three targeted covalent inhibitor-like molecules (compounds 3a-3c) against Ivyp1. Specifically, our scaffold makes use of a non-covalent driving group, aliphatic linkers, and a rhenium(I)-based warhead to direct covalent modification at a biologically relevant site. NMR-guided characterizations of synthetic intermediates (compounds 1a-1c) with Ivyp1 support a potential mechanism of drug-based inhibition; however, solubility issues prevented similar protein-based investigations with compounds (3a-3c), ultimately obstructing our progress. In all, this work builds the foundation for a drug discovery campaign against P. aeruginosa—in which a novel, drug-based modulator of peptidoglycan biology is discovered—while also highlighting frequent obstacles in drug and antibiotic discovery. Future experiments will expand on our synthetic results and pursue structure-activity relationships.