Department of Physics and Earth Sciences and ‡Department of Life Sciences and Chemistry, Jacobs University Bremen , 28759 Bremen, Germany.
J Phys Chem B. 2018 Feb 1;122(4):1417-1426. doi: 10.1021/acs.jpcb.7b12568. Epub 2018 Jan 22.
In Gram-negative bacteria, the lack or quenching of antibiotic translocation across the outer membrane is one of the main factors for acquiring antibiotic resistance. An atomic-level comprehension of the key features governing the transport of drugs by outer-membrane protein channels would be very helpful in developing the next generation of antibiotics. In a previous study [ J. D. Prajapati et al. J. Chem. Theory Comput. 2017 , 13 , 4553 ], we characterized the diffusion pathway of a ciprofloxacin molecule through the outer membrane porin OmpC of Escherichia coli by combining metadynamics and a zero-temperature string method. Here, we evaluate the diffusion route through the OmpC porin for a similar fluoroquinolone, that is, the enrofloxacin molecule, using the previously developed protocol. As a result, it was found that the lowest-energy pathway was similar to that for ciprofloxacin; namely, a reorientation was required on the extracellular side with the carboxyl group ahead before enrofloxacin reached the constriction region. In turn, the free-energy basins for both antibiotics are located at similar positions in the space defined by selected reaction coordinates, and their affinity sites share a wide number of porin residues. However, there are some important deviations due to the chemical differences of these two drugs. On the one hand, a slower diffusion process is expected for enrofloxacin, as the permeation pathway exhibits higher overall energy barriers, mainly in the constriction region. On the other hand, enrofloxacin needs to replace some polar interactions in its affinity sites with nonpolar ones. This study demonstrates how minor chemical modifications can qualitatively affect the translocation mechanism of an antibiotic molecule.
在革兰氏阴性菌中，抗生素跨外膜转运的缺失或淬灭是获得抗生素耐药性的主要因素之一。原子水平上理解控制外膜蛋白通道药物转运的关键特征将非常有助于开发下一代抗生素。在之前的一项研究中[J. D. Prajapati 等人。J. Chem. Theory Comput. 2017, 13, 4553]，我们通过组合元动力学和零温字符串方法，描述了环丙沙星分子通过大肠杆菌外膜孔蛋白 OmpC 的扩散途径。在这里，我们使用先前开发的方案评估了恩诺沙星分子通过 OmpC 孔蛋白的扩散途径。结果发现，最低能量途径与环丙沙星相似；即，在恩诺沙星到达缩窄区之前，需要在细胞外侧进行重新定向，使羧基在前。反过来，两种抗生素的自由能盆地在所选反应坐标定义的空间中位于相似位置，它们的亲和位点共享大量孔蛋白残基。然而，由于这两种药物的化学差异，存在一些重要的偏差。一方面，预计恩诺沙星的扩散过程会更慢，因为渗透途径表现出更高的总能量障碍，主要在缩窄区。另一方面，恩诺沙星需要用非极性取代其亲和位点中的一些极性相互作用。本研究表明，化学修饰的微小变化如何定性地影响抗生素分子的转运机制。
