Inhibition of the Bacterial Heme Oxygenases from Pseudomonas aeruginosa and Neisseria meningitidis: Novel Antimicrobial Targets
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- 作者：Lena M. Furci ; Pedro Lopes ; Suntara Eakanunkul ; Shijun Zhong ; Alexander D. MacKerell ; Jr. ; Angela Wilks
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：August 9, 2007
- 年：2007
- 卷：50
- 期：16
- 页码：3804 - 3813
- 全文大小：376K
- 年卷期：v.50,no.16(August 9, 2007)
- ISSN：1520-4804
文摘
The final step in heme utilization and iron acquisition in many pathogens is the oxidative cleavage of hemeby heme oxygenase (HO), yielding iron, biliverdin, and carbon monoxide. Thus, the essential requirementfor 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 inhibitorsof the Neisseria meningitidis HO (nm-HO). CADD virtual screening applied to 800 000 compounds identified153 for biological assay. Several of the compounds were shown to have KD values in the micromolar rangefor 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 combinedwith experimental analysis has been used to identify novel inhibitors of the bacterial heme oxygenases thatcan cross the cell membrane and specifically inhibit HO activity.