Folate Inhibitors - Antimicrobics That Act on Cell Wall Synthesis

Folate Inhibitors

Agents that interfere with synthesis of folic acid by bacteria have selective toxicity be-cause mammalian cells are unable to accomplish this feat and use preformed folate from dietary sources. Folic acid is derived from para-aminobenzoic acid (PABA), glu-tamate, and a pteridine unit. In its reduced form, it is an essential coenzyme for the transport of one-carbon compounds in the synthesis of purines, thymidine, some amino acids, and, thus, indirectly of nucleic acids and proteins. The major inhibitors of the folate pathway are the sulfonamides, trimethoprim, para-aminosalicylic acid, and the sulfones.

Sulfonamides Sulfonamides are structural analogs of PABA and compete with it for theenzyme (dihydropteroate synthetase) that combines PABA and pteridine in the initial stage of folate synthesis. This blockage has multiple effects on the bacterial cells; the most im-portant of these is disruption of nucleic acid synthesis. The effect is bacteriostatic, and the addition of PABA to a medium that contains sulfonamide neutralizes the inhibitory effect and allows growth to resume.

When introduced in the 1940s, sulfonamides had a very broad spectrum (staphylo-cocci, streptococci, many Gram-negative bacteria) but resistance developed quickly, and this has restricted their use for systemic infections. Now their primary use is for uncompli-cated urinary tract infections caused by members of the Enterobacteriaceae, particularly Escherichia coli. Sulfonamides are convenient for this purpose because they are inexpen-sive, well absorbed by the oral route, and excreted in high levels in the urine.

Trimethoprim-Sulfamethoxazole Trimethoprim acts on the folate synthesis pathwaybut at a point after sulfonamides. It competitively inhibits the activity of bacterial dihydrofolate reductase, which catalyzes the conversion of folate to its reduced active coenzyme form. When combined with sulfamethoxazole, a sulfonamide, trimethoprim leads to a two-stage blockade of the folate pathway, which often results in synergistic bacteriostatic or bactericidal effects. This quality is exploited in therapeutic prepara-tions that combine both agents in a fixed proportion designed to yield optimum synergy.

Trimethoprim-sulfamethoxazole (TMP-SMX) has a much broader and stable spec-trum than either of its components alone; this includes most of the common pathogens, whether they are Gram-positive or Gram-negative, cocci or bacilli. Anaerobes and P. aeruginosa are exceptions. It is also active against some uncommon agents such as Nocardia. TMP-SMX is widely and effectively used in the treatment of urinary tract in-fections, otitis media, sinusitis, prostatitis, and infectious diarrhea, and it the agent of choice for pneumonia caused by Pneumocystis carinii, a fungus.