Date of Award

5-2009

Document Type

Thesis

Degree Name

Master of Science (MS)

Program

Biomedical Sciences

Track

Cell Biology and Biochemistry

Research Advisor

Stephen White, PhD

Committee

Richard Lee, PhD Susan Senogles, PhD

Keywords

Antibiotic Resistance, Dihydropteroate Synthase, Sulfamethoxazole, X-ray Crystallography

Abstract

The goal of this study is to develop small molecule inhibitors of DHPS for the treatment of a variety of infectious diseases. According to the World Health Organization (WHO), infectious diseases kill more than 13 million people worldwide every year making it the second leading cause of death behind cardiovascular disease. The sulfonamide class of drugs has been in use since the 1930’s to treat many infectious agents and act by targeting the enzyme dihydropteroate synthase (DHPS) of the prokaryotic and lower eukaryotic folate pathway.

DHPS is an ideal drug target because humans do not synthesize folate de novo and is a well validated system. However, the emergence of bacterial resistance has limited the efficacy of sulfonamides, and an increasing trend in drug resistance has heightened the need for development of new therapeutics. Although drug resistance has severely limited the clinical use of sulfonamides, the folate pathway, and DHPS in particular, remain an ideal target for therapeutic development. This is due to the fact that DHPS accommodates two substrates, para-aminobenzoic acid (pABA) and 6-hydroxymethyl-7,8-dihydropterin-pyrophosphate (DHPPP), which bind to separate and distinct regions of the protein. Sulfonamides act by binding the pABA pocket composed largely of dynamic loop regions which fold in upon substrate binding to complete the active site. In contrast, the pterin pocket is a highly conserved, rigid binding site, and is predicted to be more suitable for the development of small molecule inhibitors. Therefore, we propose targeting the pterin binding site as a means of developing novel small molecule inhibitors of DHPS.

The advantages of this method are that pterin binds to a distinct region of DHPS separate from the pABA binding site and removed from areas known to accommodate sulfonamide resistance. In addition, it provides a novel approach to exploit a well validated drug target. We hypothesize that pterin-based compounds will provide a new class of antibiotics that will overcome the problems of drug resistance and provide novel therapeutics for a broad spectrum of infectious diseases.

DOI

10.21007/etd.cghs.2009.0020

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