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首页> 外文期刊>Biochemistry >Toward Screening for Antibiotics with Enhanced Permeation Properties through Bacterial Porins
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Toward Screening for Antibiotics with Enhanced Permeation Properties through Bacterial Porins

机译：旨在通过细菌孔蛋白筛选具有增强渗透性的抗生素

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Gram-negative bacteria are protected by an outer membrane barrier, and to reach their periplasmicntarget, penicillins have to diffuse through outermembrane porins such asOmpF.Here we propose a structure-ndynamics-based strategy for improving such antibiotic uptake. Using a variety of experiments (high-resolutionnsingle channel recording,Minimum Inhibitory Concentration (MIC), liposome swelling assay) and acceleratednmolecular simulations,we decipher the subtle balance of interactions governing ampicillin diffusion through thenporin OmpF. This suggests mutagenesis of a hot spot residue of OmpF for which additional simulations revealndrastic changes in the molecular and energetic pathway of ampicillin’s diffusion. Inverting the problem, wenpredict and describe how benzylpenicillin diffuses with a lower effective energy barrier by interacting differentlynwith OmpF. The thorough comparison between the theoretical predictions and the three independentnexperiments, which were set up to measure the kinetics of transport and biological activity, gives insights onnhow to combine such different investigation techniques with the aim of providing complementary validation.nOur study illustrates the importance of microscopic interactions at the constriction region of the biologicalnchannel to control the antibiotic flux through it.We conclude by providing a complete inventory of the channelnand antibiotic hot spots and discuss the implications in terms of antibacterial screening and design
机译：革兰氏阴性细菌受到外膜屏障的保护，为了达到其周质靶标，青霉素必须通过诸如OmpF的外膜孔蛋白扩散。通过各种实验（高分辨率单通道记录，最小抑菌浓度（MIC），脂质体溶胀试验）和加速分子模拟，我们破译了当时通过孔蛋白OmpF控制氨苄青霉素扩散的相互作用的微妙平衡。这暗示了OmpF热点残基的诱变，对此进行了进一步的模拟，揭示了氨苄青霉素扩散的分子和能量途径中的变化。反过来，通过与OmpF的不同相互作用，预测并描述苄青霉素如何以较低的有效能垒扩散。通过对理论预测和三个独立实验之间的彻底比较，来测量运输和生物活性的动力学，从而提供了有关如何将不同的研究技术结合起来以提供补充验证的见解。n我们的研究表明了微观研究的重要性通过提供完整的通道和抗生素热点清单，最后讨论了生物通道收缩区域的相互作用，以控制通过它的抗生素通量。并讨论了抗菌筛选和设计的意义

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