Identification of borinic esters as inhibitors of bacterial cell growth and bacterial methyltransferases, CcrM and MenH.
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.
Benkovic
Stephen J
SJ
Department of Chemistry, The Pennsylvania State University, 414 Wartik Laboratory, University Park, Pennsylvania 16802, USA. sjb1@psu.edu
Baker
Stephen J
SJ
Alley
M R K
MR
Woo
Youn-Hi
YH
Zhang
Yong-Kang
YK
Akama
Tsutomu
T
Mao
Weimin
W
Baboval
Justin
J
Rajagopalan
P T Ravi
PT
Wall
Mark
M
Kahng
Lyn Sue
LS
Tavassoli
Ali
A
Shapiro
Lucy
L
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
D000900:Anti-Bacterial Agents; D001889:Borinic Acids; D004952:Esters; D015254:DNA Modification Methylases