Inhibition of the bacterial heme oxygenases from Pseudomonas aeruginosa and Neisseria meningitidis: novel antimicrobial targets.
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 KD 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.
Furci
Lena M
LM
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, MD 21201-1140, USA.
Lopes
Pedro
P
Eakanunkul
Suntara
S
Zhong
Shijun
S
MacKerell
Alexander D
AD
Wilks
Angela
A
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001664:Biliverdine / Q000096:biosynthesis; D016208:Databases, Factual; D003959:Diamines / Q000737:chemistry / Q000494:pharmacology; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology; D009345:Neisseria meningitidis / Q000201:enzymology*; D011485:Protein Binding; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000201:enzymology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D003959:Diamines; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D011725:Pyridines; D004159:Diphenylamine; D006419:Heme Oxygenase (Decyclizing); D001664:Biliverdine