Competitive Inhibitors

Many of the synthetic chemotherapeutic agents (synthetic antibiotics) are competitive inhibitors of essential metabolites or growth factors that are needed in bacterial metabolism.  Hence, these types of antimicrobial agents are sometimes referred to as anti-metabolites or growth factor analogs, since they are designed to specifically inhibit an essential metabolic pathway in the bacterial pathogen. At a chemical level, competitive inhibitors are structurally similar to a bacterial growth factor or metabolite, but they do not fulfill their metabolic function in the cell. Some are bacteriostatic and some are bactericidal. Their selective toxicity is based on the premise that the bacterial pathway does not occur in the host.

Sulfonamides were introduced as chemotherapeutic agents by Domagk in 1935, who showed that one of these compounds (prontosil) had the effect of curing mice with infections caused by beta-hemolytic streptococci. Chemical modifications of the compound sulfanilamide gave rise to compounds with even higher and broader antibacterial activity. The resulting sulfonamides have broadly similar antibacterial activity, but differ widely in their pharmacological actions. Bacteria which are almost always sensitive to the sulfonamides include Streptococcus pneumoniae, beta-hemolytic streptococci and E. coli. The sulfonamides have been extremely useful in the treatment of uncomplicated UTI caused by E. coli, and in the treatment of meningococcal meningitis (because they cross the blood-brain barrier).

The sulfonamides (e.g. Gantrisin and Trimethoprim) are inhibitors of the bacterial enzymes required for the synthesis of tetrahydofolic acid (THF), the vitamin form of folic acid essential for 1-carbon transfer reactions. Sulfonamides are structurally similar to para aminobenzoic acid (PABA), the substrate for the first enzyme in the THF pathway, and they competitively inhibit that step. Trimethoprim is structurally similar to dihydrofolate (DHF) and competitively inhibits the second step in THF synthesis mediated by the DHF reductase. Animal cells do not synthesize their own folic acid but obtain it in a preformed fashion as a vitamin. Since animals do not make folic acid, they are not affected by these drugs, which achieve their selective toxicity for bacteria on this basis.

The chemical structures of sulfanilamide and para-aminobenzoic acid (PABA). In bacteria, sulfanilamide acts as a competitive inhibitor of the enzyme dihydropteroate synthetase, DHPS, which catalyses the conversion of PABA to dihydropteroate, a key step in folate synthesis. Folate is necessary for the cell to synthesize nucleic acids (DNA and RNA), and in its absence, cells will be unable to divide. Hence, sulfanilamide and other sulfonamides exhibit a bacteriostatic rather than bactericidal effect.