DHPs

Dihydropteroate synthase (DHPS) is an enzyme in the folate (tetrahydrofolate) biosynthesis pathway found in many bacteria, archaea, plants, and some algae. Humans and other animals lack a functional DHPS, making the enzyme a common target for selective antibacterial therapy. The gene encoding DHPS in bacteria is typically folP.

DHPS catalyzes the condensation of p-aminobenzoic acid (PABA) with dihydropteridine pyrophosphate to form dihydropteroate and pyrophosphate. This reaction channels substrates toward dihydrofolate and ultimately tetrahydrofolate, which are essential cofactors for one-carbon transfer reactions and nucleotide biosynthesis. The enzyme operates in the cytosol and often functions as a homomeric complex, with a catalytic site that coordinates the substrates through conserved residues.

In clinical contexts, DHPS is targeted by sulfonamide antibiotics (for example, sulfamethoxazole). These compounds act as competitive inhibitors that mimic PABA, thereby blocking folate synthesis in bacteria. Sulfonamides are frequently used in combination therapies (notably with trimethoprim, which inhibits dihydrofolate reductase) to produce a synergistic antibacterial effect.

Resistance to DHPS inhibitors can arise through mutations in folP that reduce drug binding, acquisition of alternative DHPS variants with lower affinity, or alterations that increase intracellular PABA levels. Such resistance mechanisms are a frequent cause of decreased antibiotic efficacy and are a focus of ongoing research.

Overall, DHPS is a validated and widely studied target in antimicrobial drug design due to its essential role in microbial folate biosynthesis and the absence of a direct human counterpart.