HIV-1 Integrase Inhibitor-Inspired Antibacterials Targeting Isoprenoid Biosynthesis

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• 作者：Yonghui Zhang ; Fu-Yang Lin ; Kai Li ; Wei Zhu ; Yi-Liang Liu ; Rong Cao ; Ran Pang ; Eunhae Lee ; Jordan Axelson ; Mary Hensler ; Ke Wang ; Katie J. Molohon ; Yang Wang ; Douglas A. Mitchell ; Victor Nizet ; Eric Oldfield
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：May 10, 2012
• 年：2012
• 卷：3
• 期：5
• 页码：402-406
• 全文大小：399K
• 年卷期：v.3,no.5(May 10, 2012)
• ISSN：1948-5875

文摘

We report the discovery of antibacterial leads, keto- and diketo-acids, targeting two prenyl transferases: undecaprenyl diphosphate synthase (UPPS) and dehydrosqualene synthase (CrtM). The leads were suggested by the observation that keto- and diketo-acids bind to the active site Mg²⁺/Asp domain in HIV-1 integrase, and similar domains are present in prenyl transferases. We report the X-ray crystallographic structures of one diketo-acid and one keto-acid bound to CrtM, which supports the Mg²⁺ binding hypothesis, together with the X-ray structure of one diketo-acid bound to UPPS. In all cases, the inhibitors bind to a farnesyl diphosphate substrate-binding site. Compound 45 had cell growth inhibition MIC₉₀ values of 250鈥?00 ng/mL against Staphylococcus aureus, 500 ng/mL against Bacillus anthracis, 4 渭g/mL against Listeria monocytogenes and Enterococcus faecium, and 1 渭g/mL against Streptococcus pyogenes M1 but very little activity against Escherichia coli (DH5伪, K12) or human cell lines.

Keywords:

antibacterials; isoprenoid biosynthesis; HIV integrase; undecaprenyl diphosphate synthase; dehydrosqualene synthase