Polysaccharide deacetylases serve as new targets for the design of inhibitors against Bacillus anthracis and Bacillus cereus |
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Authors: | Stavroula Balomenou Dimitris Koutsioulis Anastasia Tomatsidou Mary Tzanodaskalaki Kyriacos Petratos Vassilis Bouriotis |
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Affiliation: | 1. Institute of Molecular Biology & Biotechnology – Foundation for Research & Technology-Hellas N. Plastira 100, Heraklion 70013, Greece;2. Department of Biology Voutes, University Campus University of Crete, Heraklion 70013, Greece |
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Abstract: | Peptidoglycan N-acetylglucosamine (GlcNAc) deacetylases (PGNGdacs) from bacterial pathogens are validated targets for the development of novel antimicrobial agents. In this study we examined the in vitro inhibition of hydroxamate ligand N-hydroxy-4-(naphthalene-1-yl)benzamide (NHNB), a selective inhibitor of histone deacetylases-8 (HDAC8), against two PGNGdacs namely BC1974 and BC1960 from B. cereus, highly homologous to BA1977 and BA1961 of B. anthracis, respectively. Kinetic analysis showed that this compound functions as a competitive inhibitor of both enzymes with apparent Ki’s of 8.7?μM (for BC1974) and 66?μM (for BC1960), providing thus the most potent CE4 inhibitor reported to date. NHNB was tested in antibacterial assays and showed bactericidal activity against both examined pathogens acting as a multi-target drug. This compound can serve as lead for the development of inhibitors targeting the conserved active sites of the multiple polysaccharide deacetylases (PDAs) of both pathogens. |
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Keywords: | Hydroxamic acids Lysozyme sensitivity Bactericidal activity Polysaccharide deacetylases Peptidoglycan deacetylases |
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