Streptococcus pneumoniae Isoprenoid Biosynthesis Is Downregulated by Diphosphomevalonate: An Antimicrobial Target

详细信息    查看全文

• 作者：John L. Andreassi ; II ; Kristina Dabovic ; and Thomas S. Leyh
• 刊名：Biochemistry
• 出版年：2004
• 出版时间：December 28, 2004
• 年：2004
• 卷：43
• 期：51
• 页码：16461 - 16466
• 全文大小：79K
• 年卷期：v.43,no.51(December 28, 2004)
• ISSN：1520-4995

文摘

The toll that Streptococcus pneumoniae exacts on the welfare of humanity is enormous. Thisorganism claims the lives of ~3700 people daily, the majority of whom are children below the age of 5,and the situation could worsen due to the increasing incidence of pernicious, multiple-antibiotic-resistantstrains. Here we report the discovery and characterization of a new allosteric site, shown to be absent inhumans, that can be used to switch off an essential pathway in S. pneumoniae, the mevalonate pathway.Diphosphomevalonate (DPM), an intermediate in the pathway, binds with high affinity (K_d = 530 nM)to mevalonate kinase, the first enzyme in the pathway, and inactivates it. Steady-state and equilibriumbinding measurements reveal that DPM binding is noncompetitive versus substrates. DPM binds at anallosteric site, and inhibition cannot be overcome by an increasing substrate concentration. The DPM-binding site is a promising target for the development of new antimicrobial agents.