The development of new antibiotics with activity towards a broad spectrum of bacteria, including multiresistant strains, is a very important topic for global public health. As part of previous works, N-benzenesulfonyl-1,2,3,4-tetrahydroquinoline (BSTHQ) derivatives were described as antimicrobial agents active against gram-positive and gram-negative pathogens. In this work, experimental and molecular modelling studies were performed in order to identify their potential biological target in the light of structure-based design efforts towards further BSTHQ derivatives. First, a carboxyfluorescein leakage assay was performed using liposomes to mimic bacterial membranes, which found no significative membrane disruption effects with respect to control samples. These results support a non-surfactant antimicrobial activity of the tested compounds. In a second stage, the inhibition of potential antimicrobial targets was screened using molecular modelling methods, taking into account previously reported druggable targets deposited in the ChEMBL database for Escherichia coli and Staphylococcus aureus. Two enzymes, namely D-glutamic acid-adding enzyme (MurD) and N-acetylglucosamine-1-phophate-uridyltransferase (GlmU), both involved in bacterial membrane synthesis, were identified as potential targets. Pharmacodynamic interaction models were developed using known MurD and GlmU inhibitors by applying state-of-the-art chemoinformatic methods (molecular docking, molecular dynamics and free energy of interaction analyses). These models were further extended to the analysis of the studied BSTHQ derivatives. Overall, our results demonstrated that the studied BSTHQ derivatives elicit their antibacterial activity by interacting with a specific molecular target, GlmU being the highly feasible one. Based on the presented results, further structure-aided design efforts towards the obtaining of novel BSTHQ derivatives are envisioned.

Communicated by Ramaswamy H. Sarma

对全球细菌，包括多种耐药菌株在内的多种细菌具有活性的新抗生素的开发是非常重要的课题。作为先前作品的一部分，N-苯磺酰基-1,2,3,4-四氢喹啉（BSTHQ）衍生物被描述为对革兰氏阳性和革兰氏阴性病原体具有活性的抗菌剂。在这项工作中，进行了实验和分子建模研究，以便根据针对进一步的BSTHQ衍生物的基于结构的设计努力，确定其潜在的生物学靶标。首先，使用脂质体模拟细菌膜来进行羧基荧光素渗漏试验，发现该膜对对照样品没有明显的膜破坏作用。这些结果支持了所测试化合物的非表面活性剂抗菌活性。在第二阶段，使用分子建模方法筛选了潜在的抗菌靶标的抑制作用，大肠杆菌和金黄色葡萄球菌。两种酶，即D-谷氨酸加成酶（MurD）和N均参与细菌膜合成的β-乙酰氨基葡萄糖-1-磷酸-尿苷基转移酶（GlmU）被确定为潜在的靶标。通过使用最新的化学信息学方法（分子对接，分子动力学和相互作用自由能分析），使用已知的MurD和GlmU抑制剂开发了药效相互作用模型。这些模型进一步扩展到所研究的BSTHQ衍生物的分析。总体而言，我们的结果表明，所研究的BSTHQ衍生物通过与特定的分子靶标相互作用而引发其抗菌活性，GlmU是高度可行的靶标。根据提出的结果，可以设想进一步的结构辅助设计工作，以获取新型的BSTHQ衍生物。

由Ramaswamy H.Sarma沟通