title: Characterization of d-boroAla as a novel broad-spectrum antibacterial agent targeting d-Ala-d-Ala ligase.
abstract: d-boroAla was previously characterized as an inhibitor of bacterial alanine racemase and d-Ala-d-Ala ligase enzymes (Biochemistry, 28, 1989, 3541). In this study, d-boroAla was identified and characterized as an antibacterial agent. d-boroAla has activity against both Gram-positive and Gram-negative organisms, with minimal inhibitory concentrations down to 8 μg / mL. A structure-function study on the alkyl side chain (NH(2) -CHR-B(OR')(2) ) revealed that d-boroAla is the most effective agent in a series including boroGly, d-boroHomoAla, and d-boroVal. l-boroAla was much less active, and N-acetylation completely abolished activity. An LC-MS / MS assay was used to demonstrate that d-boroAla exerts its antibacterial activity by inhibition of d-Ala-d-Ala ligase. d-boroAla is bactericidal at 1× minimal inhibitory concentration against Staphylococcus aureus and Bacillus subtilis, which each encode one copy of d-Ala-d-Ala ligase, and at 4× minimal inhibitory concentration against Escherichia coli and Salmonella enterica serovar Typhimurium, which each encode two copies of d-Ala-d-Ala ligase. d-boroAla demonstrated a frequency of resistance of 8 × 10(-8) at 4× minimal inhibitory concentration in S. aureus. These results demonstrate that d-boroAla has promising antibacterial activity and could serve as the lead agent in a new class of d-Ala-d-Ala ligase targeted antibacterial agents. This study also demonstrates d-boroAla as a possible probe for d-Ala-d-Ala ligase function.
authors.affiliation: Division of Pharmaceutical Sciences, University of Missouri, Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Putty
authors.forename: Aman
authors.initials: A
authors.lastname: Rai
authors.forename: Darshan
authors.initials: D
authors.lastname: Jamindar
authors.forename: Paul
authors.initials: P
authors.lastname: Pagano
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Quinn
authors.forename: Takehiko
authors.initials: T
authors.lastname: Mima
authors.forename: Herbert P
authors.initials: HP
authors.lastname: Schweizer
authors.forename: William G
authors.initials: WG
authors.lastname: Gutheil
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects; D001897:Boronic Acids / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012486:Salmonella typhimurium / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001897:Boronic Acids; C569930:boroalanine; D010453:Peptide Synthases; C019638:D-alanylalanine synthetase; D000409:Alanine