Inhibition of 2,3-oxidosqualene-lanosterol cyclase in Candida albicans by pyridinium ion-based inhibitors.
The N-(4E,8E)-5,9,13-trimethyl-4,8,12-tetradecatrien-1- ylpyridinium and N-(4E,8E)-5,9,13-trimethyl-4,8,12-tetradecatrien-1- ylpicolinium cations were evaluated for their ability to inhibit 2,3-oxidosqualene-lanosterol cyclase activity in Candida albicans. Both compounds inhibited fungal growth, were fungicidal, and resulted in the accumulation of squalene epoxide concurrent with a decrease in ergosterol, monomethyl sterols, and lanosterol, as was expected for the specific inhibition of 2,3-oxidosqualene-lanosterol cyclase activity. These compounds are electron-poor aromatic mimics of a monocyclized transition state or high-energy intermediate formed from oxidosqualene, which may explain their selective action.
Goldman
R C
RC
Anti-infective Research Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA. robert.goldman@abbott.com
Zakula
D
D
Capobianco
J O
JO
Sharpe
B A
BA
Griffin
J H
JH
D000666:Amphotericin B / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology; D004352:Drug Resistance, Microbial; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004875:Ergosterol / Q000096:biosynthesis; D015725:Fluconazole / Q000494:pharmacology; D019751:Intramolecular Transferases; D007535:Isomerases / Q000037:antagonists & inhibitors*; D011726:Pyridinium Compounds / Q000494:pharmacology*
D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D011726:Pyridinium Compounds; D000666:Amphotericin B; D015725:Fluconazole; D007535:Isomerases; D019751:Intramolecular Transferases; C021924:lanosterol synthase; D004875:Ergosterol