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Antimicrobial Agents and Chemotherapy, July 1998, p. 1581-1586, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Decreased Accumulation or Increased Isoleucyl-tRNA Synthetase Activity Confers Resistance to the Cyclic beta -Amino Acid BAY 10-8888 in Candida albicans and Candida tropicalis

Karl Ziegelbauer*

Bayer AG, Institut für Antiinfektiva Forschung, D-42096 Wuppertal, Germany

Received 14 January 1998/Returned for modification 5 March 1998/Accepted 3 May 1998

BAY 10-8888, a cyclic beta -amino acid, exerts its antifungal activity by inhibition of isoleucyl-tRNA synthetase activity after accumulation to a millimolar concentration inside the cell. We have selected and characterized BAY 10-8888-resistant Candida albicans mutants. Reduced BAY 10-8888 accumulation as well as increased isoleucyl-tRNA synthetase activity was observed in these mutants. Some of the mutants were cross-resistant to cispentacin, a structurally related beta -amino acid, while sensitivities to 5-fluorocytosine and fluconazole remained unchanged in all mutants. All except two in vitro-resistant mutants were pathogenic in a murine candidiasis model, and BAY 10-8888 failed to cure the infection. Furthermore, we have characterized BAY 10-8888 transport and isoleucyl-tRNA synthetase activity in several Candida tropicalis strains which showed MICs higher than those of other Candida strains. An analysis of the C. tropicalis strains revealed that intracellular concentrations of BAY 10-8888 were in the millimolar range, comparable to those for C. albicans. However, these isolates expressed isoleucyl-tRNA synthetase activities about fourfold higher than those for C. albicans. To test the possibility of resistance modeling, we determined the correlations between the intracellular concentration of BAY 10-8888, the specific activity of isoleucyl-tRNA synthetase, the number of free, i.e., noninhibited, isoleucyl-tRNA synthetase molecules/cell, and growth, assuming a linear relation. We found significant correlations between growth and the intracellular concentration of BAY 10-8888 and between growth and the number of free isoleucyl-tRNA synthetase molecules/cell, but not between growth and the specific activity of isoleucyl-tRNA synthetase.

* Corresponding author. 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, July 1998, p. 1581-1586, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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