Antibacterial Strategies Targeting Dihydrofolate Reductase
Summary
Dihydrofolate reductase (DHFR) occupies a central node in the bacterial folate biosynthetic pathway, catalysing the reduction of dihydrofolate to tetrahydrofolate, a precursor for thymidine, purines and several amino acids. Inhibitors of DHFR have proved highly effective as antibacterial agents due to their capacity to arrest DNA synthesis and cell division. Traditional antifolates such as trimethoprim exploit subtle structural differences between prokaryotic and eukaryotic DHFR, but rising resistance through point mutations and horizontal gene transfer has underlined the need for next-generation inhibitors. Contemporary strategies encompass structure-guided design of novel scaffolds with improved affinity and selectivity, exploration of polypharmacology within the folate pathway to enhance potency and reduce resistance, and the development of chiral or stereospecific compounds that can overcome common resistance mutations. Advances in X-ray crystallography, computational modelling and fragment screening have facilitated the identification of nonclassical binding sites and allosteric pockets, while combination therapies that pair DHFR inhibitors with blockers of adjacent enzymes in folate biosynthesis promise synergistic antibacterial effects. Collectively, these efforts aim to deliver potent, broad-spectrum agents with robust activity against methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pyogenes and other priority pathogens, thereby addressing a critical global health challenge.
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Antibacterial Strategies Targeting Dihydrofolate Reductase publication trend
The graph below shows the total number of articles in antibacterial strategies targeting dihydrofolate reductase across all publications each year (not limited to Nature Index journals).
Technical terms
Dihydrofolate reductase (DHFR): Enzyme that reduces dihydrofolate to tetrahydrofolate, essential for nucleotide and amino acid synthesis in bacteria.
Antifolate: Small-molecule inhibitor that mimics folate substrates to block enzymes within the folate biosynthetic pathway.
Propargyl-linked antifolate (PLA): A class of DHFR inhibitors incorporating a propargyl spacer to enhance binding specificity and potency.
Polypharmacology: Therapeutic strategy that targets multiple enzymes or pathways simultaneously to improve efficacy and prevent resistance.
Minimal inhibitory concentration (MIC): Lowest concentration of an antimicrobial required to prevent visible growth of a microorganism in vitro.
References
- Utility of the Biosynthetic Folate Pathway for Targets in Antimicrobial Discovery. Antibiotics (2014).
- Toward New Therapeutics for Skin and Soft Tissue Infections: Propargyl-Linked Antifolates Are Potent Inhibitors of MRSA and Streptococcus pyogenes. PLOS ONE (2012).
- Chiral evasion and stereospecific antifolate resistance in Staphylococcus aureus. PLOS Computational Biology (2022).
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