All ETDs from UAB

Advisory Committee Chair

Sadanandan E Velu

Advisory Committee Members

Wayne J Brouillette

Aaron L Lucius

Narayana Vl Sthanam

Norbert Schormann

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

Staphylococcus aureus (S. aureus) is the causative organism for a wide range of infectious diseases from superficial skin infections to dangerous bacteremias. Six pathogens named ESKAPE pathogens are responsible for majority of antibiotic resistant bacterial infections. MRSA is the single most prevalent ESKAPE pathogen. Many of the nosocomial MRSA strains are multi-drug resistant, and even methicillin-sensitive strains can be deadly. S. aureus has recently taken on a new role in causing an escalating number of community-acquired infections in non-hospitalized persons without predisposing risk factors. Due to the increase in the number of infections caused by multi-drug resistant S. aureus and its possible use as a biowafare / bioterrorism agent, new therapeutic agents acting through novel mechanisms are sorely needed. This research project is directed towards the discovery of new inhibitors of S. aureus surface enzyme, sortase A (SrtA) as potential antibacterial agents to treat S. aureus infections. Sortases play a crucial role in the early stages of S. aureus pathogenesis by modulating bacterium's ability to adhere to host tissues via surface proteins anchored to the bacterial cell wall. Specifically, SrtA catalyzes the cleavage of the amide bond between threonine and glycine of the LPETG structural motif of surface proteins during cell wall anchoring. Thus, inhibiting the function of SrtA can disrupt the formation of surface protein assembly and make the bacteria less virulent. S. aureus mutants lacking SrtA are reported to be defective in establishing infection in animal models. Thus, SrtA is a valid target for the discovery of drugs that act against S. aureus. Utilizing the high resolution X-ray crystal structures of S. aureus SrtA and its complex with substrate LPETG, we have conducted inhibitor design studies to identify new inhibitors of SrtA. In silico virtual screening of commercial small molecule libraries against the SrtA active site using the software, FlexX resulted in the identification of several new low micromolar inhibitors of SrtA. Structure activity relationship studies on these lead compounds has led to improvement in enzyme inhibitory activity. Additional studies have been conducted to gain insight in to the molecular mechanism of SrtA inhibition by the lead compounds.

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