Date of Completion

5-30-2018

Embargo Period

5-29-2020

Keywords

Antifolates, multidrug resistance, gram-negative bacteria, dihydrofolate reductase, plasmid-aquired resistance, E. coli, trimethoprim

Major Advisor

Dennis Wright

Associate Advisor

Victoria Robinson

Associate Advisor

José Manautou

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Antibiotic resistance has limited our ability to treat life-threatening infections putting pressure on the scientific community to discover new effective therapeutics. There have been significant research efforts to develop drugs for the treatment of infections caused by Gram-negative pathogens as they are the leading cause of healthcare-associated infections and have a high propensity to accumulate antibiotic resistance genes. The two major challenges to Gram-negative antibiotic development are finding drug chemotypes that are able to penetrate the cell envelope and accounting for plasmid-associated resistance genes. We have developed a novel class of antifolates, designated as propargyl-linked antifolates, as effective antimicrobials against multidrug resistant Enterobacteriaceae, the leading cause of antibiotic resistant Gram-negative infections. Propargyl-linked antifolates are inhibitors of dihydrofolate reductase (DHFR) and derivatives of trimethoprim, a commonly prescribed DHFR inhibitor. Resistance to trimethoprim is conferred by a family of >30 naturally resistant DHFR and has limited its effectiveness. Through structure-based drug design, we have determined the mechanism by which propargyl-linked antifolates inhibit both trimethoprim-sensitive and resistant DHFR. In our design, we employed substrate-envelope constraints to expand the spectrum of activity of propargyl-linked antifolates such that they are potent inhibitors of multiple trimethoprim-resistant DHFRs. In all, these efforts have led to a comprehensive understanding of trimethoprim resistance and the development of inhibitors that overcome these mechanisms.

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