Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/197118
Type: Artigo de periódico
Title: Molecular Graphics Approach To Bacterial Acrb Protein-beta-lactam Antibiotic Molecular Recognition In Drug Efflux Mechanism.
Author: Kiralj, Rudolf
Ferreira, Márcia M C
Abstract: AcrAB-TolC is the most important multidrug efflux pump system of Gram-negative bacteria, responsible for their resistance to lipophilic and amphiphilic drugs. In this work, a molecular graphics study of the pump components AcrB and TolC, 16 beta-lactam antibiotics and 7 other substrates, as well as of AcrB-substrate complexes, was performed in order to give a mechanistic proposal for the efflux process at molecular level. AcrAB-TolC is a proton-dependent electromechanical device which opens to extrude drugs from the bacterial periplasm and perhaps cytoplasm, by means of a series of structural changes within the complex and its components AcrA, AcrB and TolC. These changes are initiated by protonation and disruption of salt bridges and certain hydrogen bonds, and are followed by conformational changes in which a number of intra- and interchain interactions are rearranged. Molecular properties of beta-lactams accounting for their lipophilicity, shape/conformation and other sterical features, polar/charge group distribution and other electronic properties, and hydrogen bonding potency determine their interaction with polar headpieces of the inner membrane, recognition and binding to receptors of AcrB and TolC. The orientation of the beta-lactam molecular dipoles with respect the efflux system is maintained during the drug efflux. Elongated cylinder-like beta-lactam antibiotics with lipophylic side chains, a significantly negative component of the dipole moment and low hydrogen bonding capacity seem to be good substrates of AcrAB-TolC.
Subject: Bacterial Proteins
Biological Transport
Carrier Proteins
Gram-negative Bacteria
Models, Molecular
Quantitative Structure-activity Relationship
Substrate Specificity
Beta-lactams
Rights: fechado
Identifier DOI: 10.1016/j.jmgm.2005.10.010
Address: http://www.ncbi.nlm.nih.gov/pubmed/16406715
Date Issue: 2006
Appears in Collections:Unicamp - Artigos e Outros Documentos

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