Inhibition of the Bacterial Heme Oxygenases from Pseudomonas aeruginosa and Neisseria meningitidis:  Novel Antimicrobial Targets

• Published in: Journal of medicinal chemistry Vol. 50; no. 16; pp. 3804 - 3813
• Main Authors: Furci, Lena M, Lopes, Pedro, Eakanunkul, Suntara, Zhong, Shijun, MacKerell, Alexander D, Wilks, Angela
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 09.08.2007
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biliverdine - biosynthesis; Biological and medical sciences; Databases, Factual; Diamines - chemistry; Diamines - pharmacology; Diphenylamine - analogs & derivatives; Diphenylamine - chemistry; Diphenylamine - pharmacology; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - enzymology; Escherichia coli - genetics; Heme Oxygenase (Decyclizing) - antagonists & inhibitors; Heme Oxygenase (Decyclizing) - chemistry; Medical sciences; Models, Molecular; Naphthalenes - chemistry; Naphthalenes - pharmacology; Neisseria meningitidis; Neisseria meningitidis - enzymology; Pharmacology. Drug treatments; Protein Binding; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - enzymology; Pyridines - chemistry; Pyridines - pharmacology; Structure-Activity Relationship; Pseudomonadales; Organic hydrazide; Enzyme; Neisseriaceae; Benzene derivatives; Heme oxygenase (decyclizing); Enzyme inhibitor; Inhibitor enzyme complex; Aniline derivatives; Neisseria meningitidis; In vitro; Modeling; Carboxylic acid; Vinylic compound; Molecular model; Bacteria; Micrococcales; Pseudomonadaceae; Carboxamide; Pseudomonas aeruginosa; Oxidoreductases; Hydrazone; Antibacterial agent
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0700969

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.