Antibiotic resistance is a rapidly evolving health concern that requires a sustained effort to understand mechanisms of resistance and develop new agents that overcome those mechanisms. The dihydrofolate reductase (DHFR) inhibitor, trimethoprim (TMP), remains one of the most important orally administered antibiotics. However, resistance through chromosomal mutations and mobile, plasmid-encoded insensitive DHFRs threatens the continued use of this agent. We are pursuing the development of new propargyl-linked antifolate (PLA) DHFR inhibitors designed to evade these mechanisms. While analyzing contemporary TMP-resistant clinical isolates of methicillin-resistant and sensitive Staphylococcus aureus, we discovered two mobile resistance elements, dfrG and dfrK. This is the first identification of these resistance mechanisms in the United States. These resistant organisms were isolated from a variety of infection sites, show clonal diversity and each contain distinct resistance genotypes for common antibiotics. Several PLAs showed significant very potent activity against these resistant strains by direct inhibition of the TMP resistance elements.

Propargyl-linked antifolates potently inhibit US clinical S. aureus isolates with newly identified dfrG and dfrK resistance genes

253rd National Meeting (2017)

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