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Tackling vancomycin-resistant bacteria with 'lipophilic-vancomycin-carbohydrate conjugates'

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dc.contributor.author Yarlagadda, Venkateswarlu
dc.contributor.author Konai, Mohini M.
dc.contributor.author Manjunath, Goutham B.
dc.contributor.author Ghosh, Chandradhish
dc.contributor.author Haldar, Jayanta
dc.date.accessioned 2017-01-04T09:09:00Z
dc.date.available 2017-01-04T09:09:00Z
dc.date.issued 2015
dc.identifier.citation Journal of Antibiotics en_US
dc.identifier.citation 68 en_US
dc.identifier.citation 5 en_US
dc.identifier.citation Yarlagadda, V.; Konai, M. M.; Manjunath, G. B.; Ghosh, C.; Haldar, J., Tackling vancomycin-resistant bacteria with 'lipophilic-vancomycin-carbohydrate conjugates'. J. Antibiot. 2015, 68 (5), 302-312. en_US
dc.identifier.issn 0021-8820
dc.identifier.uri https://libjncir.jncasr.ac.in/xmlui/10572/2010
dc.description Restricted access en_US
dc.description.abstract Vancomycin, a glycopeptide antibiotic, has long been a drug of choice for life-threatening Gram-positive bacterial infections. Vancomycin confers its antibacterial activity by inhibiting bacterial cell wall biosynthesis. However, over the time, vancomycin has also been rendered ineffective by vancomycin-resistant bacteria (VRB). These bacteria developed resistance to it by alteration of cell wall precursor from D-Ala-D-Ala to D-Ala-D-Lac (vancomycin-resistant Enterococci, VRE), which leads to manifold reduction in the binding constant and results in the loss of antibacterial activity. Herein, we report various vancomycin-sugar analogs, based on a simple design rationale, which exhibit increased binding affinity to VRB, thereby resensitizing VRB to vancomycin. Optimized vancomycin-sugar conjugate exhibited 150-fold increase in affinity for N, N'-diacetyl-Lys-D-Ala-D-Lac compared with vancomycin. This improved binding affinity was also reflected in its antibacterial activity, wherein the MIC value was brought down from 750 to 36 mu M against VRE (VanA phenotype). To further sensitize against VRE, we appended lipophilic alkyl chain to optimized vancomycin-sugar conjugate. This lipophilic-vancomycin-sugar conjugate was 41000-fold (MIC= 0.7 mu M) and 250-fold (MIC= 1 mu M) more effective against VanA and VanB strains of VRE, respectively, compared with vancomycin. Therefore, this synthetically simple approach could lead to the development of new generation of glycopeptide antibiotics, which can be clinically used to tackle VRB infections. en_US
dc.description.uri http://dx.doi.org/10.1038/ja.2014.144 en_US
dc.language.iso English en_US
dc.publisher Japan Antibiotics Research Association en_US
dc.rights ?Japan Antibiotics Research Association, 2015 en_US
dc.subject Biotechnology & Applied Microbiology en_US
dc.subject Immunology en_US
dc.subject Microbiology en_US
dc.subject Pharmacology & Pharmacy en_US
dc.subject ALA-D-ALA en_US
dc.subject Semisynthetic Glycopeptide Antibiotics en_US
dc.subject Hydrophobic Side-Chains en_US
dc.subject D-Lac Binding en_US
dc.subject Antibacterial Activity en_US
dc.subject Staphylococcus-Aureus en_US
dc.subject Antimicrobial Activity en_US
dc.subject Derivatives en_US
dc.subject Analogs en_US
dc.subject Lipoglycopeptide en_US
dc.title Tackling vancomycin-resistant bacteria with 'lipophilic-vancomycin-carbohydrate conjugates' en_US
dc.type Article en_US


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