Microbial natural products as a source of antifungals.
The vast number and variety of chemotherapeutic agents isolated from microbial natural products and used to treat bacterial infections have greatly contributed to the improvement of human health during the past century. However, only a limited number of antifungal agents (polyenes and azoles, plus the recently introduced caspofungin acetate) are currently available for the treatment of life-threatening fungal infections. Furthermore, the prevalence of systemic fungal infections has increased significantly during the past decade. For this reason, the development of new antifungal agents, preferably with novel mechanisms of action, is an urgent medical need. A selection of antifungal agents in early stages of development, produced by micro-organisms, is summarized in this review. The compounds are classified according to their mechanisms of action, covering inhibitors of the synthesis of cell wall components (glucan, chitin and mannoproteins), of sphingolipid synthesis (serine palmitoyltransferase, ceramide synthase, inositol phosphoceramide synthase and fatty acid elongation) and of protein synthesis (sordarins). In addition, some considerations related to the chemotaxonomy of the producing organisms and some issues relevant to antifungal drug discovery are also discussed.
Vicente
M F
MF
Centro de Investigacíon Básica, Merck Research Laboratories, Merck, Sharp and Dohme España, S. A. Josefa Valcárcel 38, 28027 Madrid, Spain. Francisca_vicente@merck.com
Basilio
A
A
Cabello
A
A
Peláez
F
F
D000818:Animals; D000900:Anti-Bacterial Agents / Q000302:isolation & purification / Q000494:pharmacology; D000935:Antifungal Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001393:Azoles / Q000302:isolation & purification / Q000494:pharmacology; D001688:Biological Products / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000077336:Caspofungin; D002686:Chitin / Q000037:antagonists & inhibitors; D054714:Echinocandins; D005936:Glucans / Q000037:antagonists & inhibitors; D006801:Humans; D055666:Lipopeptides; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D009181:Mycoses / Q000188:drug therapy; D010455:Peptides; D010456:Peptides, Cyclic; D011090:Polyenes / Q000302:isolation & purification / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D013107:Sphingolipids / Q000037:antagonists & inhibitors
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D001393:Azoles; D001688:Biological Products; D054714:Echinocandins; D005936:Glucans; D055666:Lipopeptides; D008562:Membrane Glycoproteins; D010455:Peptides; D010456:Peptides, Cyclic; D011090:Polyenes; D011500:Protein Synthesis Inhibitors; D013107:Sphingolipids; C025363:mannoproteins; D002686:Chitin; D000077336:Caspofungin