Antimetabolites

Antimetabolites target the synthesis of a metabolite that is required for normal metabolism and survival of the pathogen. Sulfa drugs, such as sulfamethoxazole and sulfadiazine, in combination with trimethoprim are the most widely used antimetabolites. Sulfa drugs inhibit the folate biosynthesis pathway by targeting the enzyme dihydropteroate synthetase (DHPS). Trimethoprim targets the same pathway, but at a different enzyme called dihydrofolate reductase (DHFR). As such, both drugs display synergy that can easily be visualized using the strip diffusion test. The inhibition of DHFR and DHPS can be observed using a simple NADPH/NADP \({ }^{+}\) colorimetric assay. Resistance to antimetabolites is conferred by mutations to DHPS and DHFR, DHFR overexpression, chromosomal recombination to incorporate new DHPS genes, and by multidrug efflux pumps.