Journal
ACS INFECTIOUS DISEASES
Volume 3, Issue 6, Pages 421-427Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.7b00005
Keywords
peptidoglycan; autolysin; N-acetylglucosaminidase; inhibitor; diamide
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Funding
- Institutional Development Award (IDeA) Network for Biomedical Research Excellence from the National Institute of General Medical Sciences of the National Institutes of Health [P20GM103430]
- Brown University
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [1464538] Funding Source: National Science Foundation
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N-Acetylglucosaminidases (GlcNAcases) play an important role in the remodeling and recycling of bacterial peptidoglycan by degrading the polysaccharide backbone. Genetic deletions of autolysins can impair cell division and growth, suggesting an opportunity for using small molecule autolysin inhibitors both as tools for studying the chemical biology of autolysins and also as antibacterial agents. We report here the synthesis and evaluation of a panel of diamides that inhibit the growth of Bacillus subtilis. Two compounds, fgkc (21) and fgka (5), were found to be potent inhibitors (MIC 3.8 +/- 1.0 and 21.3 +/- 0.1 mu M, respectively). These compounds inhibit the B. subtilis family 73 glycosyl hydrolase LytG, an exo GlcNAcase. Phenotypic analysis of fgkc (21)-treated cells demonstrates a propensity for cells to form linked chains, suggesting impaired cell growth and division.
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