Document Detail


Characterization of d-boroAla as a novel broad-spectrum antibacterial agent targeting d-Ala-d-Ala ligase.
MedLine Citation:
PMID:  21827632     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Sandeep Putty; Aman Rai; Darshan Jamindar; Paul Pagano; Cheryl L Quinn; Takehiko Mima; Herbert P Schweizer; William G Gutheil
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-09-21
Journal Detail:
Title:  Chemical biology & drug design     Volume:  78     ISSN:  1747-0285     ISO Abbreviation:  Chem Biol Drug Des     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-10-14     Completed Date:  2012-02-13     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  101262549     Medline TA:  Chem Biol Drug Des     Country:  England    
Other Details:
Languages:  eng     Pagination:  757-63     Citation Subset:  IM    
Copyright Information:
© 2011 John Wiley & Sons A/S.
Affiliation:
Division of Pharmaceutical Sciences, University of Missouri, Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA.
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MeSH Terms
Descriptor/Qualifier:
Alanine / analogs & derivatives*,  chemistry,  pharmacology
Anti-Bacterial Agents / chemistry,  pharmacology*
Bacillus subtilis / drug effects
Boronic Acids / chemistry,  pharmacology*
Escherichia coli / drug effects
Microbial Sensitivity Tests
Peptide Synthases / antagonists & inhibitors*,  metabolism
Salmonella typhimurium / drug effects
Staphylococcus aureus / drug effects
Structure-Activity Relationship
Grant Support
ID/Acronym/Agency:
AI065357/AI/NIAID NIH HHS; GM060149/GM/NIGMS NIH HHS; K2303015//PHS HHS; R01 GM060149-05/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Bacterial Agents; 0/Boronic Acids; 0/boroalanine; 56-41-7/Alanine; EC 6.3.2.-/Peptide Synthases; EC 6.3.2.4/D-alanylalanine synthetase
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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