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Antimicrobial Agents and Chemotherapy, September 1998, p. 2197-2205, Vol. 42, No. 9
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Molecular Mode of Action of the Antifungal beta -Amino Acid BAY 10-8888

Karl Ziegelbauer,1,* Peter Babczinski,2 and Wolfgang Schönfeld1

Institut für Antiinfektiva Forschung, Bayer AG, D-42096 Wuppertal,1 and Institut für Metabolismusforschung und Rückstandanalytik, Bayer AG, D-40789 Monheim,2 Germany

Received 9 February 1998/Returned for modification 4 June 1998/Accepted 17 June 1998

BAY 10-8888 is a cyclic beta -amino acid that is related to cispentacin and that has antifungal activity. Candida albicans cells accumulated BAY 10-8888 intracellularly to a concentration about 200 that in the medium when grown in media with a variety of nitrogen sources. In complex growth medium, BAY 10-8888 transport activity was markedly reduced and was paralleled by a decrease in its antifungal activity. Uptake of BAY 10-8888 was mediated by an H+-coupled amino acid transporter with specificity for branched-chain amino acids (isoleucine, leucine, and valine) and showed a KT (Michaelis constant of the transport reaction) of 0.95 mM and a Vmax of 18.9 nmol × min-1 × 107 cells-1. Similar to the transport of natural amino acids in Saccharomyces cerevisiae, the transport of BAY 10-8888 into the cell was unidirectional. Efflux occurred by diffusion and was not carrier mediated. Inside the cell BAY 10-8888 inhibited specifically isoleucyl-tRNA synthetase, resulting in inhibition of protein synthesis and cell growth. Intracellular isoleucine reversed BAY 10-8888-induced growth inhibition. BAY 10-8888 was not incorporated into proteins. BAY 10-8888 inhibited isoleucyl-tRNA synthetase with the same concentration dependency as protein biosynthesis in intact cells assuming 200-fold accumulation.

* Corresponding author. Present mailing address: Bayer Yakuhin Ltd., Research Center Kyoto, 6-5-1-3 Kunimidai, Kizu-cho, Soraku-gun, Kyoto, 619-02, Japan. Phone: (81)774 75-2462. Fax: (81)774 75-2507. E-mail: karl.ziegelbauer.kz{at}bayer-ag.de.

Antimicrobial Agents and Chemotherapy, September 1998, p. 2197-2205, Vol. 42, No. 9
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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