Date of Completion

1-5-2017

Embargo Period

1-5-2017

Keywords

Antifolates, Drug Resistance, Antibiotic Resistance, Antibiotic Discovery, Medicinal Chemistry, MRSA

Major Advisor

Dennis Wright

Associate Advisor

Victoria L Robinson

Associate Advisor

Jeffrey R. Aeschlimann

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Resistance to every class of antibiotics has been identified clinically. The rapid development and spread of resistance is responsible for the diminished lifetime of many once efficacious therapeutics. Trimethoprim (TMP), a clinically important dihydrofolate reductase (DHFR) inhibitor, remains a first line treatment for Staphylococcus aureus infections but its continued use is threatened by the emergence of resistance. Identifying and understanding the mechanisms of trimethoprim resistance is crucial for the development for novel antibiotics to overcome the contemporary clinical resistances. Trimethoprim resistance is conferred through both the acquisition of mutations in the endogenous DHFR enzyme and of innately resistant enzymes. Guided by structure based drug design, a novel class of DHFR inhibitors, known as propargyl-linked antifolates (PLAs), has been developed to directly overcome trimethoprim resistance in Staphylococcus aureus. By doing this, we identified the contemporary mechanisms of antifolate resistance, developed a molecular understanding of reported and prospective mutational resistance mechanisms and generated a class of potent inhibitors against both wild type and TMPR DHFR enzymes and S. aureus strains. In addition to their potent activity, these inhibitors also reveal unique binding and plasticity of both the inhibitor and co-factor binding sites, leading to the discovery of a novel NADPH configuration. In all, these efforts led to a comprehensive understanding of antifolate S. aureus and the development of potent inhibitors that overcome these resistance mechanisms.

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