Designed to penetrate: Time-resolved interaction of single antibiotic molecules with bacterial pores
Designed to penetrate: Time-resolved interaction of single antibiotic molecules with bacterial pores
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DOI：
10.1073/pnas.152206799
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发表时间：
2002-07-23
影响因子：
11.1
通讯作者：
Bezrukov, SM
中科院分区：
文献类型：
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作者：
Nestorovich, EM;Danelon, C;Bezrukov, SM
膜渗透性屏障是导致细菌对抗生素产生内在耐药性的因素之一。我们已经能够分解单个氨苄西林分子通过一般细菌孔蛋白的通道，OmpF（外膜蛋白F），被认为是β -内酰胺类抗生素的主要途径。通过离子通道重构和高分辨率电导记录，我们发现氨苄西林和其他几种有效的青霉素和头孢菌素与OmpF通道收缩区的残留物强烈相互作用。因此，我们假设，与进化为结合某些代谢物分子的底物特异性通道类似，抗生素已经“进化”为通道特异性。分子模型表明氨苄西林分子的电荷分布与细菌孔蛋白最窄部分的电荷分布互补。这些电荷的相互作用在通道内产生一个吸引区域，促进药物通过收缩区转运，并导致更高的通透率。
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.