Date of Completion
Antifolates, multidrug resistance, gram-negative bacteria, dihydrofolate reductase, plasmid-aquired resistance, E. coli, trimethoprim
Field of Study
Doctor of Philosophy
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.
Lombardo, Michael, "Novel Antifolates to Target Antibiotic Resistant Gram-negative Pathogens" (2018). Doctoral Dissertations. 1938.