Abstract：
:Antibiotic resistance is a rapidly evolving health concern that requires a sustained effort to understand mechanisms of resistance and to 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 activity against these resistant strains by direct inhibition of the TMP resistance elements.
journal_name
Cell Chem Bioljournal_title
Cell chemical biologyauthors
Reeve SM,Scocchera EW,G-Dayanadan N,Keshipeddy S,Krucinska J,Hajian B,Ferreira J,Nailor M,Aeschlimann J,Wright DL,Anderson ACdoi
10.1016/j.chembiol.2016.11.007subject
Has Abstractpub_date
2016-12-22 00:00:00pages
1458-1467issue
12eissn
2451-9456issn
2451-9448pii
S2451-9456(16)30430-5journal_volume
23pub_type
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