title: Sulfa and trimethoprim-like drugs - antimetabolites acting as carbonic anhydrase, dihydropteroate synthase and dihydrofolate reductase inhibitors.
abstract: Recent advances in microbial genomics, synthetic organic chemistry and X-ray crystallography provided opportunities to identify novel antibacterial targets for the development of new classes of antibiotics and to design more potent antimicrobial compounds derived from existing antibiotics in clinical use for decades. The antimetabolites, sulfa drugs and trimethoprim (TMP)-like agents, are inhibitors of three families of enzymes. One family belongs to the carbonic anhydrases, which catalyze a simple but physiologically relevant reaction in all life kingdoms, carbon dioxide hydration to bicarbonate and protons. The other two enzyme families are involved in the synthesis of tetrahydrofolate (THF), i.e. dihydropteroate synthase (DHPS) and dihydrofolate reductase. The antibacterial agents belonging to the THF and DHPS inhibitors were developed decades ago and present significant bacterial resistance problems. However, the molecular mechanisms of drug resistance both to sulfa drugs and TMP-like inhibitors were understood in detail only recently, when several X-ray crystal structures of such enzymes in complex with their inhibitors were reported. Here, we revue the state of the art in the field of antibacterials based on inhibitors of these three enzyme families.
authors.affiliation: Istituto di Biochimica delle Proteine - CNR , Napoli , Italy and.
authors.forename: Clemente
authors.initials: C
authors.lastname: Capasso
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000963:Antimetabolites / Q000138:chemical synthesis / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000737:chemistry*; D004094:Dihydropteroate Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D013424:Sulfanilamides / Q000138:chemical synthesis / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry*; D014295:Trimethoprim / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D000963:Antimetabolites; D001426:Bacterial Proteins; D002257:Carbonic Anhydrase Inhibitors; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D013424:Sulfanilamides; D014295:Trimethoprim; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D002256:Carbonic Anhydrases
keywords: Antibacterial; carbonic anhydrase; dihydrofolate reductase; dihydropteroate synthase; sulfa drug; trimethoprim