Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy.
Department of Pharmaceutical Sciences, "Department of excellence 2018-2022", University of Perugia, Via del Liceo 1, 06123 Perugia, Italy.
Int J Mol Sci. 2019 Aug 19;20(16):4041. doi: 10.3390/ijms20164041.
The use and misuse of antibiotics has resulted in critical conditions for drug-resistant bacteria emergency, accelerating the development of antimicrobial resistance (AMR). In this context, the co-administration of an antibiotic with a compound able to restore sufficient antibacterial activity may be a successful strategy. In particular, the identification of efflux pump inhibitors (EPIs) holds promise for new antibiotic resistance breakers (ARBs). Indeed, bacterial efflux pumps have a key role in AMR development; for instance, NorA efflux pump contributes to () resistance against fluoroquinolone antibiotics (e.g., ciprofloxacin) by promoting their active extrusion from the cells. Even though NorA efflux pump is known to be a potential target for EPIs development, the absence of structural information about this protein and the little knowledge available on its mechanism of action have strongly hampered rational drug discovery efforts in this area. In the present work, we investigated at the molecular level the substrate recognition pathway of NorA through a Supervised Molecular Dynamics (SuMD) approach, using a NorA homology model. Specific amino acids were identified as playing a key role in the efflux pump-mediated extrusion of its substrate, paving the way for a deeper understanding of both the mechanisms of action and the inhibition of such efflux pumps.
抗生素的使用和滥用导致了耐药菌紧急情况的出现，加速了抗菌药物耐药性（AMR）的发展。在这种情况下，将抗生素与能够恢复足够抗菌活性的化合物联合使用可能是一种成功的策略。特别是，鉴定外排泵抑制剂（EPIs）有望成为新的抗生素耐药性破坏剂（ARBs）。事实上，细菌外排泵在外排泵在 AMR 发展中起着关键作用；例如，NorA 外排泵通过促进其从细胞中主动排出，有助于对氟喹诺酮类抗生素（如环丙沙星）产生耐药性。尽管 NorA 外排泵被认为是 EPIs 开发的潜在靶点，但由于该蛋白缺乏结构信息，以及对其作用机制的了解甚少，严重阻碍了该领域的合理药物发现工作。在本工作中，我们使用 NorA 同源模型，通过有监督的分子动力学（SuMD）方法，在分子水平上研究了 NorA 的底物识别途径。确定了特定的氨基酸在其底物的外排泵介导的外排中起着关键作用，为深入了解作用机制和抑制这种外排泵铺平了道路。
