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Antimicrobial Agents and Chemotherapy, December 1999, p. 2950-2959, Vol. 43, No. 12
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Proton-Pumping-ATPase-Targeted Antifungal Activity of a Novel Conjugated Styryl Ketone

Elias K. Manavathu,1,* Jonathan R. Dimmock,2 Sarvesh C. Vashishtha,2 and Pranatharthi H. Chandrasekar1

Division of Infectious Diseases, Department of Medicine, Wayne State University, Detroit, Michigan 48201,1 and College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5C92

Received 1 March 1999/Returned for modification 13 April 1999/Accepted 21 September 1999

NC1175 (3-[3-(4-chlorophenyl)-2-propenoyl]-4-[2-(4-chlorophenyl)vinylene]-1-ethyl-4-piperidinol hydrochloride) is a novel thiol-blocking conjugated styryl ketone that exhibits activity against a wide spectrum of pathogenic fungi. Incubation of NC1175 with various concentrations of cysteine and glutathione eliminated its antifungal activity in a concentration-dependent fashion. Since NC1175 is a lipophilic compound that has the potential to interact with cytoplasmic membrane components, we examined its effect on the membrane-located proton-translocating ATPase (H+-ATPase) of yeast (Candida albicans, Candida krusei, Candida guilliermondii, Candida glabrata, and Saccharomyces cerevisiae) and Aspergillus (Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus, and Aspergillus nidulans) species. The glucose-induced acidification of external medium due to H+-ATPase-mediated expulsion of intracellular protons by these fungi was measured in the presence of several concentrations of the drug. NC1175 (12.5 to 50 µM) inhibited acidification of external medium by Candida, Saccharomyces, and Aspergillus species in a concentration-dependent manner. Vanadate-inhibited hydrolysis of ATP by membrane fractions of C. albicans was completely inhibited by 50 µM NC1175, suggesting that the target of action of NC1175 in these fungi may include H+-ATPase.

* Corresponding author. Mailing address: Department of Medicine, Wayne State University, 427 Lande Building, Detroit, MI 48201. Phone: (313) 577-1931. Fax: (313) 993-0302. E-mail: aa1388{at}wayne.edu.

Antimicrobial Agents and Chemotherapy, December 1999, p. 2950-2959, Vol. 43, No. 12
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Afeltra, J., Vitale, R. G., Mouton, J. W., Verweij, P. E. (2004). Potent Synergistic In Vitro Interaction between Nonantimicrobial Membrane-Active Compounds and Itraconazole against Clinical Isolates of Aspergillus fumigatus Resistant to Itraconazole. Antimicrob. Agents Chemother. 48: 1335-1343 [Abstract] [Full Text]  
  • Manavathu, E. K., Dimmock, J. R., Vashishtha, S. C., Chandrasekar, P. H. (2001). Inhibition of H+-ATPase-mediated proton pumping in Cryptococcus neoformans by a novel conjugated styryl ketone. J Antimicrob Chemother 47: 491-494 [Abstract] [Full Text]  


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