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Toward Broad Spectrum Dihydrofolate Reductase Inhibitors Targeting Trimethoprim Resistant Enzymes Identified in
Stephanie M Reeve1, Debjani Si1, Jolanta Krucinska1
1Department of Pharmaceutical Sciences , University of Connecticut , 69 N. Eagleville Road , Storrs , Connecticut 06269 , United States.
Abstract:
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.
Insights
Novel antifolates combat trimethoprim-resistant Staphylococcus aureus. New ionized nonclassical antifolates (INCAs) show potent activity against DHFR enzymes, offering a promising strategy against MRSA infections.
Area of Science:
- Medicinal Chemistry
- Microbiology
- Structural Biology
Background:
- Plasmid-borne resistance enzymes in *Staphylococcus aureus* diminish the efficacy of dihydrofolate reductase (DHFR) inhibitors like trimethoprim and iclaprim.
- The rise of trimethoprim-resistant (TMPR) and methicillin-resistant *Staphylococcus aureus* (MRSA) necessitates new therapeutic strategies targeting DHFR.
Purpose of the Study:
- To develop a novel class of antifolates effective against resistant DHFR isoforms.
- To design compounds that retain interactions of classical antifolates while broadening activity spectrum and maintaining cell penetration.
Main Methods:
- Structure-based drug design approach.
- Biochemical, structural, and computational methods for inhibitor optimization.
- Evaluation of enzymatic and cellular activity against clinically relevant TMPR and MRSA isolates.
Main Results:
- Development of a novel class of ionized nonclassical antifolates (INCAs).
- INCAs demonstrate broad activity against pathogenic DHFR isoforms, including resistant ones.
- Optimized INCA compounds exhibit low nanomolar enzymatic activity and potent cellular efficacy.
- Compounds show high selectivity for bacterial DHFR over human isoforms.
Conclusions:
- INCAs represent a promising new class of antifolates against drug-resistant *Staphylococcus aureus*.
- The developed compounds offer a potential solution to overcome trimethoprim resistance in MRSA.
- Structure-based design successfully yielded potent and selective DHFR inhibitors.
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