Molecular mode of action of the antifungal beta-amino acid BAY 10-8888.
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 x min-1 x 10(7) 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.
Ziegelbauer
K
K
Institut für Antiinfektiva Forschung, Bayer AG, D-42096 Wuppertal, Germany. karl.ziegelbauer.kz@bayer-ag.de
Babczinski
P
P
Schönfeld
W
W
D000596:Amino Acids / Q000494:pharmacology; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001693:Biological Transport, Active; D002176:Candida albicans / Q000187:drug effects* / Q000378:metabolism; D003470:Culture Media; D003515:Cycloleucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007532:Isoleucine / Q000494:pharmacology; D007533:Isoleucine-tRNA Ligase / Q000037:antagonists & inhibitors; D014176:Protein Biosynthesis
D000596:Amino Acids; D000935:Antifungal Agents; D003470:Culture Media; D007532:Isoleucine; D003515:Cycloleucine; D007533:Isoleucine-tRNA Ligase; C114614:2-amino-4-methylenecyclopentane-1-carboxylic acid