Date of Award

Summer 6-25-2023

Track

Chemistry

Degree Type

Thesis

Degree Name

Master of Science in Chemical Sciences (MSCB)

Department

Chemistry

Committee Chair/First Advisor

Dr. Thomas C. Leeper

Committee Member

Dr. Meredith Baker

Committee Member

Dr. Mohammad Halim

Abstract

Pseudomonas aeruginosa (P. aeruginosa) is a Gram-negative bacterium that causes blood and lung infections in hospital environments due to its ability to survive on improperly sterilized medical equipment. P. aeruginosa has developed several multi-drug resistance mechanisms that make it very difficult to treat with current antibiotics.1 This presents the need for a new class of antibiotics that cannot be overcome by P. aeruginosa’s mechanisms of resistance.

The primary goal of this project was to develop a small library of inhibitors that could later be incorporated into lead compounds for novel antibiotic drug discovery. One of P. aeruginosa’s main adaptations for survival is a periplasmic protein called the inhibitor of vertebrate lysozyme protein 1 (Ivyp1). This protein helps the bacterium evade attack from the host’s immune system. P. aeruginosa produces Ivyp1 when its cell wall is damaged. Ivyp1 then prevents lysozymes from hydrolyzing the peptidoglycan that makes up the bacterial cell wall.2 A class of drugs targeted covalent inhibitors (TCIs) were chosen as the weapon for fighting Ivyp1. TCIs are molecules that form a covalent bond between a nucleophilic atom on the target protein and an electrophilic atom on the TCI itself.3 This irreversible binding prevents the target protein, Ivyp1, from inhibiting lysozyme.A library of small, organic warheads were combined with Ivyp1 and subsequently, the reaction was monitored with complementary techniques, Nuclear Magnetic Resonance (NMR) and Mass spectrometry (MS). These methods gave evidence to the theory that every warhead tested, except the spiro-epoxide based warhead, interacted with Histidine 20 in Ivyp1’s active site to some degree.

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