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|Type:||Artigo de periódico|
|Title:||Molecular Graphics Approach To Bacterial Acrb Protein-β-lactam Antibiotic Molecular Recognition In Drug Efflux Mechanism|
|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 β-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 β-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 β-lactam molecular dipoles with respect the efflux system is maintained during the drug efflux. Elongated cylinder-like β-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. © 2005 Elsevier Inc. All rights reserved.|
|Appears in Collections:||Unicamp - Artigos e Outros Documentos|
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