Mogi Tatsushi, Ui Hideaki, Shiomi Kazuro, Omura Satoshi, Miyoshi Hideto, Kita Kiyoshi
Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Biochim Biophys Acta. 2009 Feb;1787(2):129-33. doi: 10.1016/j.bbabio.2008.11.016. Epub 2008 Dec 10.
To counter antibiotic-resistant bacteria, we screened the Kitasato Institute for Life Sciences Chemical Library with bacterial quinol oxidase, which does not exist in the mitochondrial respiratory chain. We identified five prenylphenols, LL-Z1272beta, gamma, delta, epsilon and zeta, as new inhibitors for the Escherichia coli cytochrome bd. We found that these compounds also inhibited the E. coli bo-type ubiquinol oxidase and trypanosome alternative oxidase, although these three oxidases are structurally unrelated. LL-Z1272beta and epsilon (dechlorinated derivatives) were more active against cytochrome bd while LL-Z1272gamma, delta, and zeta (chlorinated derivatives) were potent inhibitors of cytochrome bo and trypanosome alternative oxidase. Thus prenylphenols are useful for the selective inhibition of quinol oxidases and for understanding the molecular mechanisms of respiratory quinol oxidases as a probe for the quinol oxidation site. Since quinol oxidases are absent from mammalian mitochondria, LL-Z1272beta and delta, which are less toxic to human cells, could be used as lead compounds for development of novel chemotherapeutic agents against pathogenic bacteria and African trypanosomiasis.
为对抗抗生素耐药细菌,我们用线粒体呼吸链中不存在的细菌喹啉氧化酶对北里生命科学化学文库进行了筛选。我们鉴定出5种异戊烯基酚,即LL-Z1272β、γ、δ、ε和ζ,它们是大肠杆菌细胞色素bd的新型抑制剂。我们发现这些化合物也能抑制大肠杆菌bo型泛醌氧化酶和锥虫交替氧化酶,尽管这三种氧化酶在结构上并无关联。LL-Z1272β和ε(脱氯衍生物)对细胞色素bd的活性更高,而LL-Z1272γ、δ和ζ(氯化衍生物)是细胞色素bo和锥虫交替氧化酶的有效抑制剂。因此,异戊烯基酚可用于选择性抑制喹啉氧化酶,并作为喹啉氧化位点的探针来理解呼吸喹啉氧化酶的分子机制。由于哺乳动物线粒体中不存在喹啉氧化酶,对人类细胞毒性较小的LL-Z1272β和δ可作为开发抗病原菌和非洲锥虫病新型化疗药物的先导化合物。