Coenzyme A biosynthesis: an antimicrobial drug target.
Pantothenic acid, a precursor of coenzyme A (CoA), is essential for the growth of pathogenic microorganisms. Since the structure of pantothenic acid was determined, many analogues of this essential metabolite have been prepared. Several have been demonstrated to exert an antimicrobial effect against a range of microorganisms by inhibiting the utilization of pantothenic acid, validating pantothenic acid utilization as a potential novel antimicrobial drug target. This review commences with an overview of the mechanisms by which various microorganisms acquire the pantothenic acid they require for growth, and the universal CoA biosynthesis pathway by which pantothenic acid is converted into CoA. A detailed survey of studies that have investigated the inhibitory activity of analogues of pantothenic acid and other precursors of CoA follows. The potential of inhibitors of both pantothenic acid utilization and biosynthesis as novel antibacterial, antifungal and antimalarial agents is discussed, focusing on inhibitors and substrates of pantothenate kinase, the enzyme catalysing the rate-limiting step of CoA biosynthesis in many organisms. The best strategies are considered for identifying inhibitors of pantothenic acid utilization and biosynthesis that are potent and selective inhibitors of microbial growth and that may be suitable for use as chemotherapeutic agents in humans.
Spry
Christina
C
School of Biochemistry and Molecular Biology, The Australian National University, Canberra, Australia.
Kirk
Kiaran
K
Saliba
Kevin J
KJ
D000213:Acyl Carrier Protein / Q000502:physiology; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D018407:Bacterial Physiological Phenomena; D003065:Coenzyme A / Q000096:biosynthesis*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000378:metabolism; D005658:Fungi / Q000502:physiology; D006801:Humans; D008288:Malaria / Q000628:therapy; D010205:Pantothenic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010961:Plasmodium / Q000502:physiology
D000213:Acyl Carrier Protein; D000890:Anti-Infective Agents; D004791:Enzyme Inhibitors; D010205:Pantothenic Acid; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase; D003065:Coenzyme A