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QSAR study of β‐lactam antibiotic efflux by the bacterial multidrug resistance pump AcrB
Author(s) -
Ferreira Márcia M. C.,
Kiralj R.
Publication year - 2004
Publication title -
journal of chemometrics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.47
H-Index - 92
eISSN - 1099-128X
pISSN - 0886-9383
DOI - 10.1002/cem.867
Subject(s) - lipophilicity , quantitative structure–activity relationship , efflux , chemistry , stereochemistry , molecular descriptor , computational chemistry , combinatorial chemistry , biochemistry
Abstract AcrAB‐TolC is the most important efflux pump system of Gram‐negative bacteria, responsible for their resistance to lipophilic and amphilic drugs. In this work, HCA–PCA studies were performed to investigate the relationship between efflux activities (negative logarithm of minial inhibitor concentration, pMIC) of three strains of S. thypimurium with respect to β‐lactams, and to analyze the relationship between lipophilicity parameters calculated by different methods. The analyses demonstrate that pMICs strongly depend on properties of both bacterial strains and drug molecules, and that lipophilicity parameters do not necessarily contain the same information about the drugs. QSAR studies have shown that the calculated lipophilicities, in some cases, are non linearly related to the pMICs originated by active AcrAB‐TolC bacterial pumps, due to the existence of β‐lactams with nitrogen‐ and sulfur‐rich substituents. Among the most important β‐lactam molecular properties quantitatively related to pMICs are lipophilicity and electronic and hydrogen–bonding properties. Parameters describing these properties were included in the QSAR study to obtain parsimonius regression models for MICs. β‐Lactams were classified as good, moderately good and poor AcrAB‐TolC substrates. Their stereoelectronic molecular properties, especially the Y‐component of the molecular dipole moment and hydrogen binding properties, reflected this classification. Copyright © 2004 John Wiley & Sons, Ltd.