Ziegelbauer K, Babczinski P, Schönfeld W
Institut für Antiinfektiva Forschung, Bayer AG, D-42096 Wuppertal, Germany.
Antimicrob Agents Chemother. 1998 Sep;42(9):2197-205. doi: 10.1128/AAC.42.9.2197.
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.
BAY 10-8888是一种环状β-氨基酸，与顺戊曲菌素相关，具有抗真菌活性。白色念珠菌细胞在含有多种氮源的培养基中生长时，会在细胞内积累BAY 10-8888，其浓度约为培养基中的200倍。在复杂生长培养基中，BAY 10-8888的转运活性显著降低，同时其抗真菌活性也随之下降。BAY 10-8888的摄取由一种H⁺偶联的氨基酸转运体介导，该转运体对支链氨基酸（异亮氨酸、亮氨酸和缬氨酸）具有特异性，其米氏常数（KT）为0.95 mM，最大转运速率（Vmax）为18.9 nmol·min⁻¹·10⁷个细胞⁻¹。与酿酒酵母中天然氨基酸的转运类似，BAY 10-8888进入细胞的转运是单向的。其外流通过扩散发生，并非载体介导。在细胞内，BAY 10-8888特异性抑制异亮氨酰-tRNA合成酶，导致蛋白质合成和细胞生长受到抑制。细胞内的异亮氨酸可逆转BAY 10-8888诱导的生长抑制。BAY 10-8888不会掺入蛋白质中。假设BAY 10-8888在细胞内积累200倍，其抑制异亮氨酰-tRNA合成酶的浓度依赖性与完整细胞中蛋白质生物合成的浓度依赖性相同。
