Proton-Pumping-ATPase-targeted antifungal activity of a novel conjugated styryl ketone

NC1175 (3-[3- (4-chlorophenyl)-2-propenoyl]-4-[2-(4-chlorophenyl)vinylene]- 1-ethyl-4-piperidinol hydrochloride) is a novel thiol-blocking conjugated s tyryl ketone that exhibits activity against a wide spectrum of pathogenic f ungi. Incubation of NC1175 with various concentrations of cysteine and glut athione eliminated its antifungal activity in a concentration-dependent fas hion. Since NC1175 is a lipophilic compound that has the potential to inter act with cytoplasmic membrane components, we examined its effect on the mem brane-located proton-translocating ATPase (H+-ATPase) of yeast (Candida alb icans, Candida krusei, Candida guilliermondii, Candida glabrata, and Saccha romyces cerevisiae) and Aspergillus (Aspergillus fumigatus, Aspergillus nig er, Aspergillus flavus, and Aspergillus nidulans) species. The glucose-indu ced acidification of external medium due to H+-ATPase-mediated expulsion of intracellular protons by these fungi was measured in the presence of sever al concentrations of the drug. NC1175 (12.5 to 50 mu M) inhibited acidifica tion of external medium by Candida, Saccharomyces, and Aspergillus species in a concentration-dependent manner. Vanadate-inhibited hydrolysis of ATP b y membrane fractions of C. albicans was completely inhibited by 50 mu M NC1 175, suggesting that the target of action of NC1175 in these fungi may incl ude H+-ATPase.