Abstract
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 μM, 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.
Keywords:
N-acetylglucosaminidase; autolysin; diamide; inhibitor; peptidoglycan.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylglucosaminidase / antagonists & inhibitors*
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Acetylglucosaminidase / genetics
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Acetylglucosaminidase / metabolism
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Anti-Bacterial Agents / chemical synthesis*
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Anti-Bacterial Agents / pharmacology
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Azo Compounds / chemical synthesis*
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Azo Compounds / pharmacology
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Bacillus subtilis / drug effects*
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Bacillus subtilis / enzymology
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Bacillus subtilis / genetics
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Bacillus subtilis / growth & development
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Bacterial Proteins / antagonists & inhibitors*
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Bacterial Proteins / genetics
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Bacterial Proteins / metabolism
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Cell Division / drug effects
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology
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Gene Expression
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Hydrolysis
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Microbial Sensitivity Tests
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N-Glycosyl Hydrolases / antagonists & inhibitors*
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N-Glycosyl Hydrolases / genetics
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N-Glycosyl Hydrolases / metabolism
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Peptidoglycan / chemistry
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Structure-Activity Relationship
Substances
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Anti-Bacterial Agents
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Azo Compounds
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Bacterial Proteins
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Enzyme Inhibitors
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Peptidoglycan
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Acetylglucosaminidase
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N-Glycosyl Hydrolases