Inhibition of the bacterial heme oxygenases from Pseudomonas aeruginosa and Neisseria meningitidis:: Novel antimicrobial targets
Inhibition of the bacterial heme oxygenases from Pseudomonas aeruginosa and Neisseria meningitidis:: Novel antimicrobial targets
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DOI：
10.1021/jm0700969
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发表时间：
2007-08-09
影响因子：
7.3
通讯作者：
Wilks, Angela
中科院分区：
文献类型：
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作者：
Furci, Lena M.;Lopes, Pedro;Wilks, Angela
在许多病原体中，血红素利用和铁获取的最后一步是血红素被血红素加氧酶（HO）氧化裂解，产生铁、胆绿素和一氧化碳。因此，铁的基本需求表明，HO可能提供了一个潜在的治疗靶点的抗菌药物开发。计算机辅助药物设计（CADD）结合实验测定确定了脑膜炎奈瑟菌HO（nm-HO）的小分子抑制剂。CADD虚拟筛选应用于80万种化合物，确定了153种用于生物测定。几种化合物被证明具有K-D值在微摩尔范围内的nm-HO和铜绿假单胞菌HO（pa-HO）。这些化合物还抑制铜绿假单胞菌的生长以及在E. coli细胞中过量表达nm-HO。因此，CADD结合实验分析已被用来确定新的抑制剂的细菌血红素加氧酶，可以穿过细胞膜，并特异性地抑制HO活性。
The final step in heme utilization and iron acquisition in many pathogens is the oxidative cleavage of heme by heme, oxygenase (HO), yielding iron, biliverdin, and carbon monoxide. Thus, the essential requirement for iron suggests that HO may provide a potential therapeutic target for antimicrobial drug development. Computer-aided drug design (CADD) combined with experimental assays identified small-molecule inhibitors of the Neisseria meningitidis HO (nm-HO). CADD virtual screening applied to 800 000 compounds identified 153 for biological assay. Several of the compounds were shown to have K-D values in the micromolar range for nm-HO and the Pseudomonas aeruginosa HO (pa-HO). The compounds also inhibited the growth of P. aeruginosa as well as biliverdin formation in E. coli cells overexpressing nm-HO. Thus, CADD combined with experimental analysis has been used to identify novel inhibitors of the bacterial heme oxygenases that can cross the cell membrane and specifically inhibit HO activity.