title: MRSA Isolates from United States Hospitals Carry dfrG and dfrK Resistance Genes and Succumb to Propargyl-Linked Antifolates.
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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Storrs, CT 06269, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Reeve
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Storrs, CT 06269, USA.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Scocchera
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Storrs, CT 06269, USA.
authors.forename: Narendran
authors.initials: N
authors.lastname: G-Dayanadan
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Storrs, CT 06269, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Keshipeddy
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Storrs, CT 06269, USA.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Krucinska
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Storrs, CT 06269, USA.
authors.forename: Behnoush
authors.initials: B
authors.lastname: Hajian
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Storrs, CT 06269, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Ferreira
authors.affiliation: Department of Pharmacy Practice, University of Connecticut, 69 North Eagleville Road, Storrs, CT 06269, USA; Department of Pharmacy Services, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Nailor
authors.affiliation: Department of Pharmacy Practice, University of Connecticut, 69 North Eagleville Road, Storrs, CT 06269, USA; Division of Infectious Diseases and Department of Pharmacy Services, UConn Health/John Dempsey Hospital, 263 Farmington Avenue, Farmington, CT 06030, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Aeschlimann
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Storrs, CT 06269, USA. Electronic address: dennis.wright@uconn.edu.
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Wright
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Storrs, CT 06269, USA.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Anderson
keywords: MRSA; antibiotics; antifolate; drug discovery; drug resistance; trimethoprim