Somboon Kamolrat, Niramitranon Jitti, Pongprayoon Prapasiri
Department of Chemistry, Faculty of Science, Kasetsart University, Chatuchak, Bangkok, 10900, Thailand.
Department of Computer Engineering, Faculty of Engineering, Kasetsart University, Chatuchak, Bangkok, 10900, Thailand.
J Mol Model. 2017 Aug;23(8):227. doi: 10.1007/s00894-017-3400-2. Epub 2017 Jul 17.
Pseudomonas aeruginosa is an important nosocomial human pathogen. The major difficulty in the fight against this pathogen is the relative impermeability of its outer membrane (OM). Only specific substrates can penetrate through the OM of P. aeruginosa via substrate-specific porins, so this has become one of the most problematic drug-resistant pathogens. Carbapenems are the most effective drugs for treating P. aeruginosa infections. One such carbapenem that is applied in cases of P. aeruginosa infection is imipenem (IMI), which uses outer membrane carboxylate channel D1 (OccD1) as a point of entry into the pathogen. Unlike IMI, ertapenem (ERTA, another carbapenem) shows only weak activity towards P. aeruginosa, as it is blocked from penetrating through the OM. However, it is currently unclear as to why IMI is allowed to pass through the OM while ERTA is not. Therefore, we conducted molecular dynamics (MD) simulations to elucidate the behavior of these drugs inside OccD1 as compared to the ligand-free state. We discovered another possible binding site in the constriction region close to the side-pore opening. Both drugs employ the core lactam part to tether themselves to the binding site, whereas the tail governs the direction of permeation. L132 and F133 appear to be involved in interactions that are key to core attachment. At least four hydrogen bonds are required for drug binding. The direction of motion of L2 also plays a role: inward flipping traps IMI in the constriction area, while a shift of L2 towards the membrane brings ERTA into contact with more water, which prompts the expulsion of ERTA to the mouth of the channel protein. The opening of L2 seems to facilitate the rejection of ERTA.
铜绿假单胞菌是一种重要的医院内感染人类病原体。对抗这种病原体的主要困难在于其外膜相对不通透。只有特定的底物才能通过底物特异性孔蛋白穿过铜绿假单胞菌的外膜，因此它已成为最难对付的耐药病原体之一。碳青霉烯类是治疗铜绿假单胞菌感染最有效的药物。一种用于治疗铜绿假单胞菌感染的碳青霉烯类药物是亚胺培南（IMI），它以外膜羧酸盐通道D1（OccD1）作为进入病原体的切入点。与IMI不同，厄他培南（ERTA，另一种碳青霉烯类药物）对铜绿假单胞菌仅表现出微弱的活性，因为它被阻止穿过外膜。然而，目前尚不清楚为什么IMI能够穿过外膜而ERTA却不能。因此，我们进行了分子动力学（MD）模拟，以阐明与无配体状态相比，这些药物在OccD1内部的行为。我们在靠近侧孔开口的收缩区域发现了另一个可能的结合位点。两种药物都利用核心内酰胺部分将自身固定在结合位点上，而尾部则控制渗透方向。L132和F133似乎参与了对核心附着至关重要的相互作用。药物结合至少需要四个氢键。L2的运动方向也起作用：向内翻转将IMI捕获在收缩区域，而L2向膜的移动使ERTA与更多的水接触，这促使ERTA被排到通道蛋白的口部。L2的打开似乎有助于ERTA的排出。
