Dihydrofolate reductase (Staphylococcus aureus) (SaDHFR) (SaDHFR)

Dihydrofolate reductase (DHFR) is an essential enzyme in Staphylococcus aureus that catalyzes the reduction of 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate using NADPH as a cofactor (UniProt P0A017). This enzymatic step is crucial for the biosynthesis of thymidylate, purines, and several amino acids, making it indispensable for bacterial DNA synthesis and overall cell proliferation (PubMed PMID: 22437627). As a validated therapeutic target, SaDHFR is the primary site of action for the antibiotic trimethoprim, which is often used in combination with sulfamethoxazole to treat various staphylococcal infections (StatPearls NBK513232). However, the effectiveness of SaDHFR inhibitors is increasingly compromised by the emergence of resistant strains, often characterized by specific amino acid substitutions in the enzyme's active site or the acquisition of bypass enzymes (PubMed PMID: 28842365). Research continues into next-generation inhibitors like iclaprim, which are designed to overcome these resistance mechanisms and provide potent activity against methicillin-resistant Staphylococcus aureus (MRSA) (PubMed PMID: 29438173). This target remains a cornerstone of antimicrobial therapy despite the ongoing challenge of evolving resistance profiles in clinical isolates.

Other names

DHFRfolA5,6,7,8-tetrahydrofolate:NADP+ oxidoreductaseDihydrofolate reductase (S. aureus)

Competitive inhibition of the dihydrofolate reductase enzyme, which prevents the reduction of dihydrofolate to tetrahydrofolate, thereby depleting the essential folate pools required for the synthesis of thymidylate and purines, ultimately leading to the inhibition of bacterial DNA synthesis and cell death (PubMed PMID: 22437627, StatPearls NBK513232).