期刊
ACS INFECTIOUS DISEASES
卷 5, 期 11, 页码 1896-1906出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.9b00222
关键词
antifolate resistance; antibiotic discovery; iclaprim; drug discovery; antibiotics; ionized nonclassical antifolates
资金
- National Institutes of Health [GM118543, GM078031, AI111957, AI104841]
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-ACO276SF00515]
The spread of plasmid borne resistance enzymes in clinical Staphylococcus aureus isolates is rendering trimethoprim and iclaprim, both inhibitors of dihydrofolate reductase (DHFR), ineffective. Continued exploitation of these targets will require compounds that can broadly inhibit these resistance-conferring isoforms. Using a structure-based approach, we have developed a novel class of ionized nonclassical antifolates (INCAS) that capture the molecular interactions that have been exclusive to classical antifolates. These modifications allow for a greatly expanded spectrum of activity across these pathogenic DHFR isoforms, while maintaining the ability to penetrate the bacterial cell wall. Using biochemical, structural, and computational methods, we are able to optimize these inhibitors to the conserved active sites of the endogenous and trimethoprim resistant DHFR enzymes. Here, we report a series of INCA compounds that exhibit low nanomolar enzymatic activity and potent cellular activity with human selectivity against a panel of clinically relevant TMP resistant (TMPR) and methicillin resistant Staphylococcus aureus (MRSA) isolates.
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