Characterization of d-boroAla as a novel broad-spectrum antibacterial agent targeting d-Ala-d-Ala ligase

Sandeep Putty, Aman Rai, Darshan Jamindar, Paul Pagano, Cheryl L. Quinn, Takehiko Mima, Herbert P. Schweizer, William G. Gutheil

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 8μg/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.

Original languageEnglish
Pages (from-to)757-763
Number of pages7
JournalChemical Biology and Drug Design
Volume78
Issue number5
DOIs
Publication statusPublished - Nov 2011
Externally publishedYes

Fingerprint

Ligases
Anti-Bacterial Agents
Staphylococcus aureus
Alanine Racemase
boroalanine
Acetylation
Biochemistry
Salmonella
Salmonella enterica
Bacilli
Bacillus subtilis
Escherichia coli
Assays
Enzymes

Keywords

  • Alanine branch
  • Antibacterial
  • Broad spectrum
  • Cell wall
  • d-Ala-d-Ala ligase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Characterization of d-boroAla as a novel broad-spectrum antibacterial agent targeting d-Ala-d-Ala ligase. / Putty, Sandeep; Rai, Aman; Jamindar, Darshan; Pagano, Paul; Quinn, Cheryl L.; Mima, Takehiko; Schweizer, Herbert P.; Gutheil, William G.

In: Chemical Biology and Drug Design, Vol. 78, No. 5, 11.2011, p. 757-763.

Research output: Contribution to journalArticle

Putty, Sandeep ; Rai, Aman ; Jamindar, Darshan ; Pagano, Paul ; Quinn, Cheryl L. ; Mima, Takehiko ; Schweizer, Herbert P. ; Gutheil, William G. / Characterization of d-boroAla as a novel broad-spectrum antibacterial agent targeting d-Ala-d-Ala ligase. In: Chemical Biology and Drug Design. 2011 ; Vol. 78, No. 5. pp. 757-763.
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