Abstract：
The filamentous temperature-sensitive mutant Z protein (FtsZ), a key player in bacterial cell division machinery, emerges as an attractive target to tackle the plight posed by the ever growing antibiotic resistance over the world. Therefore in this regard, agents with scaffold diversities and broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens are highly needed. In this study, a new class of marine-derived fascaplysin derivatives has been designed and synthesized by Suzuki-Miyaura cross-coupling. Some compounds exhibited potent bactericidal activities against a panel of Gram-positive (MIC = 0.024-6.25 μg/mL) and Gram-negative (MIC = 1.56-12.5 μg/mL) bacteria including methicillin-resistant S. aureus (MRSA). They exerted their effects by dual action mechanism via disrupting the integrity of the bacterial cell membrane and targeting FtsZ protein. These compounds stimulated polymerization of FtsZ monomers and bundling of the polymers, and stabilized the resulting polymer network, thus leading to the dysfunction of FtsZ in cell division. In addition, these agents showed negligible hemolytic activity and low cytotoxicity to mammalian cells. The studies on docking and molecular dynamics simulations suggest that these inhibitors bind to the hydrophilic inter-domain cleft of FtsZ protein and the insights obtained in this study would facilitate the development of potential drugs with broad-spectrum bioactivities.
摘要：
丝状温度敏感突变体Z蛋白(FtsZ),细菌细胞分裂机制的关键角色，成为一个有吸引力的目标，以解决世界各地日益增长的抗生素耐药性所带来的困境。因此在这方面,非常需要具有支架多样性和针对革兰氏阳性和革兰氏阴性病原体的广谱抗菌活性的试剂。在这项研究中,通过Suzuki-Miyaura交叉偶联设计并合成了一类新的海洋衍生fascaplysin衍生物。一些化合物对一组革兰氏阳性（MIC=0.024-6.25μg/mL）和革兰氏阴性（MIC=1.56-12.5μg/mL）细菌表现出有效的杀菌活性，包括耐甲氧西林的金黄色葡萄球菌（MRSA）。它们通过破坏细菌细胞膜的完整性和靶向FtsZ蛋白的双重作用机制发挥其作用。这些化合物刺激了FtsZ单体的聚合和聚合物的捆扎，并稳定了所得的聚合物网络，从而导致FtsZ在细胞分裂中的功能障碍。此外,这些药物表现出可忽略的溶血活性和对哺乳动物细胞的低细胞毒性。对接和分子动力学模拟研究表明，这些抑制剂与FtsZ蛋白的亲水性域间裂隙结合，本研究中获得的见解将有助于开发具有广谱生物活性的潜在药物。
