Identification of Borinic Esters as Inhibitors of Bacterial Cell Growth and Bacterial Methyltransferases, CcrM and MenH

• Published in: Journal of medicinal chemistry 2005-11, Vol.48 (23), p.7468-7476
• Main Authors: Benkovic, Stephen J, Baker, Stephen J, Alley, M. R. K, Woo, Youn-Hi, Zhang, Yong-Kang, Akama, Tsutomu, Mao, Weimin, Baboval, Justin, Rajagopalan, P. T. Ravi, Wall, Mark, Kahng, Lyn Sue, Tavassoli, Ali, Shapiro, Lucy
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacillus subtilis; Bacillus subtilis - drug effects; Bacillus subtilis - enzymology; Biological and medical sciences; Borinic Acids - chemical synthesis; Borinic Acids - chemistry; Borinic Acids - pharmacology; Caulobacter crescentus; Caulobacter crescentus - drug effects; Caulobacter crescentus - enzymology; DNA Modification Methylases - antagonists & inhibitors; DNA Modification Methylases - chemistry; Esters - chemical synthesis; Esters - chemistry; Esters - pharmacology; Gram-Negative Bacteria - drug effects; Gram-Negative Bacteria - enzymology; Gram-Negative Bacteria - growth & development; Gram-Positive Bacteria - drug effects; Gram-Positive Bacteria - enzymology; Gram-Positive Bacteria - growth & development; Kinetics; Medical sciences; Microbial Sensitivity Tests; Pharmacology. Drug treatments; Proteobacteria - enzymology; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050676a

As bacteria continue to develop resistance toward current antibiotics, we find ourselves in a continual battle to identify new antibacterial agents and targets. We report herein a class of boron-containing compounds termed borinic esters that have broad spectrum antibacterial activity with minimum inhibitory concentrations (MIC) in the low microgram/mL range. These compounds were identified by screening for inhibitors against Caulobacter crescentus CcrM, an essential DNA methyltransferase from Gram negative α-proteobacteria. In addition, we demonstrate that borinic esters inhibit menaquinone methyltransferase in Gram positive bacteria using a new biochemical assay for MenH from Bacillus subtilis. Our data demonstrate the potential for further development of borinic esters as antibacterial agents as well as leads to explore more specific inhibitors against two essential bacterial enzymes.