title: Identification of borinic esters as inhibitors of bacterial cell growth and bacterial methyltransferases, CcrM and MenH.
abstract: 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 alpha-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.
authors.affiliation: Department of Chemistry, The Pennsylvania State University, 414 Wartik Laboratory, University Park, Pennsylvania 16802, USA. sjb1@psu.edu
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Benkovic
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Baker
authors.forename: M R K
authors.initials: MR
authors.lastname: Alley
authors.forename: Youn-Hi
authors.initials: YH
authors.lastname: Woo
authors.forename: Yong-Kang
authors.initials: YK
authors.lastname: Zhang
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Akama
authors.forename: Weimin
authors.initials: W
authors.lastname: Mao
authors.forename: Justin
authors.initials: J
authors.lastname: Baboval
authors.forename: P T Ravi
authors.initials: PT
authors.lastname: Rajagopalan
authors.forename: Mark
authors.initials: M
authors.lastname: Wall
authors.forename: Lyn Sue
authors.initials: LS
authors.lastname: Kahng
authors.forename: Ali
authors.initials: A
authors.lastname: Tavassoli
authors.forename: Lucy
authors.initials: L
authors.lastname: Shapiro
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects / Q000201:enzymology; D001889:Borinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016935:Caulobacter crescentus / Q000187:drug effects / Q000201:enzymology; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D020560:Proteobacteria / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001889:Borinic Acids; D004952:Esters; D015254:DNA Modification Methylases