FtsZ及QseC双靶标抗菌分子的设计合成及其抗菌作用与机理的研究

Infectious diseases caused by multidrug resistant bacteria have become a serious threat to human beings. Development of new antibiotic drugs with low resistance rate, is an urgent job for the research and development of novel antibiotic agent. The strategies on interfering with bacterial division or anti-virulence by inhibiting bacterial quorum sensing system, can effectively alleviate the survival pressure of bacteria and reduce their resistance on drugs. Recent studies have shown that FtsZ protein is an ideal target on inhibiting bacterial cell division and reducing resistance. And QseC is another ideal target on decreasing G- bacterial virulence production and lowering resistance. In this project, we firstly design and synthesis some novel low-resistance moleculars with double targets by conjugating FtsZ inhibitors pharmacophore and QseC ligand LED209, which could specifically block bacterial division and inhibit the expression and release of virulence genes in G- bacteria. Then we will evaluate the characters and function of these moleculars on targeting effects, G- bacterial division ability, G- bacterial virulence production, the antibacterial activity in vitro and in vivo, and further explore the underlying antibacterial mechanisms. The results will provide novel strategies for drug development in anti-multidrug resistant bacteria and new paths for the treatment of drug-resistant bacterial infections.

耐药致病菌引起的感染性疾病严重危害人类健康，研制不易诱导耐药的新型抗菌分子成为抗菌药物研发的当务之急。干扰细菌分裂或抑制细菌群体感应系统的抗毒力策略，可有效缓解细菌的生存压力，降低其耐药性。新近研究表明，FtsZ蛋白是干扰细菌细胞分裂、不易诱导细菌耐药的理想靶标；QseC是抑制G-菌毒力因子生成、不易诱导细菌耐药的理想靶标。本课题从全新的思路入手，将干扰细菌分裂的FtsZ抑制剂药效团与抑制G-菌群体感应系统QseC的抗毒力配体LED209相偶联，首次创制出全新的具有特异干扰细菌分裂、降低细菌毒力的低耐药双靶标抗G-菌分子，并对该分子展开G-细菌靶向特异性、分裂能力、毒力分泌、体内外抗菌活性及作用机理等方面研究。研究结果将为抗耐药菌药物的研制提供新思路和新策略，为耐药细菌感染治疗探索新的路径。

耐药致病菌引起的感染性疾病严重危害人类健康，研制不易诱导耐药的新型抗菌分子成为抗菌药物研发的当务之急。干扰细菌分裂或抑制细菌群体感应系统的抗毒力策略，可有效缓解细菌的生存压力，降低其耐药性。FtsZ蛋白是干扰细菌细胞分裂、不易诱导细菌耐药的理想靶标；QseC是抑制G-菌毒力因子生成、不易诱导细菌耐药的理想靶标。本研究将干扰细菌分裂的FtsZ抑制剂肉桂醛（CA）、黄连素、PC190723的衍生物与抑制G-菌群体感应系统QseC的抗毒力配体LED209衍生物相偶联，筛选出能够特异性干扰细菌分裂并降低细菌毒力的双靶标抗菌分子。研究结果显示，α溴肉桂醛（BCA）通过靶向细菌FtsZ蛋白，对所测细菌具有良好的抗菌活性；BCA结构分子中的醛基、溴取代基和双键在其抗菌活性中协同发挥重要作用；BCA能显著提高脓毒血症BALB/c小鼠生存率、延长其生存时间，显著降低重要脏器荷菌量，减轻肺和肝脏病理损伤，且无肝肾毒性。QseC阻断剂NCS-5，能够明显减少鼠伤寒沙门氏菌QseC系统下游毒力基因flhDC、sopB和sifA的表达、降低细菌鞭毛的运动能力，并有效抑制细菌对人小肠上皮细胞的侵袭和增殖能力。我们成功制备了8 个FtsZ 蛋白与QseC 蛋白双靶向抗菌分子，经抗菌活性筛选，我们确认BCA-NCS5-OH和PL（PC190723-LED209）具有双靶标抗菌特性。BCA-NCS5-OH可抑制FtsZ蛋白聚合、干扰G+细菌分裂而发挥抗G+菌作用，也能有效阻断QseC系统抑制鼠伤寒沙门菌鞭毛动力。PL一方面能显著抑制FtsZ蛋白的GTP酶活性、蛋白聚合作用和Z环在细菌中央部位的定位，进而抑制细菌分裂；另一方面PL可抑制大肠杆菌毒力基因的表达，明显抑制G-菌的鞭毛动力，并降低细菌 HeLa 细胞侵袭力和胞内增殖能力。FtsZ及QseC双靶标抗菌分子BCA-NCS5-OH和PL具有潜在的开发前景。研究结果将为抗耐药菌药物的研制提供新思路和新策略，为耐药细菌感染治疗探索新的路径。