Journal
ACS INFECTIOUS DISEASES
Volume 5, Issue 11, Pages 1896-1906Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.9b00222
Keywords
antifolate resistance; antibiotic discovery; iclaprim; drug discovery; antibiotics; ionized nonclassical antifolates
Categories
Funding
- National Institutes of Health [GM118543, GM078031, AI111957, AI104841]
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-ACO276SF00515]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available