- Characterization of d-boroAla as a novel broad-spectrum antibacterial agent targeting d-Ala-d-Ala ligase
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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 (NH2-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.
- Putty, Sandeep,Rai, Aman,Jamindar, Darshan,Pagano, Paul,Quinn, Cheryl L.,Mima, Takehiko,Schweizer, Herbert P.,Gutheil, William G.
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p. 757 - 763
(2012/07/13)
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- Crystal structure of a complex between the actinomadura R39 dd -peptidase and a peptidoglycan-mimetic boronate inhibitor: Interpretation of a transition state analogue in terms of catalytic mechanism
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The Actinomadura R39 dd-peptidase is a bacterial low molecular weight class C penicillin-binding protein. It has previously been shown to catalyze hydrolysis and aminolysis of small d-alanyl-d-alanine terminating peptides, especially those with a side cha
- Dzhekieva, Liudmila,Rocaboy, Mathieu,Kerff, Frederic,Charlier, Paulette,Sauvage, Eric,Pratt
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p. 6411 - 6419
(2011/04/16)
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