Designed to penetrate: Time-resolved interaction of single antibiotic molecules with bacterial pores

被引:263
作者
Nestorovich, EM
Danelon, C
Winterhalter, M
Bezrukov, SM
机构
[1] NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA
[2] Inst Pharmacol & Biol Struct, F-31077 Toulouse, France
[3] St Petersburg Nucl Phys Inst, Gatchina 188350, Russia
关键词
D O I
10.1073/pnas.152206799
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Membrane permeability barriers are among the factors contributing to the intrinsic resistance of bacteria to antibiotics. We have been able to resolve single ampicillin molecules moving through a channel of the general bacterial porin, OmpF (outer membrane protein F), believed to be the principal pathway for the beta-lactam antibiotics. With ion channel reconstitution and high-resolution conductance recording, we find that ampicillin and several other efficient penicillins and cephalosporins strongly interact with the residues of the constriction zone of the OmpF channel. Therefore, we hypothesize that, in analogy to substrate-specific channels that evolved to bind certain metabolite molecules, antibiotics have "evolved" to be channel-specific. Molecular modeling suggests that the charge distribution of the ampicillin molecule complements the charge distribution at the narrowest part of the bacterial porin. Interaction of these charges creates a region of attraction inside the channel that facilitates drug translocation through the constriction zone and results in higher permeability rates.
引用
收藏
页码:9789 / 9794
页数:6
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