新型LpxC抑制剂的设计合成及抗革兰阴性菌的构效关系研究

With the emergence of large numbers of drug-resistant bacteria, infection caused by bacteria, especially the multidrug resistant Gram-negative strains, becomes a great threaten to the human health once again. LpxC catalyzes the deacetylation of UDP-3-O-(R-3-hydroxymyristoyl) GlcNAc, a key step in the biosynthesis of Lipid A. Studies have shown that inhibition of LpxC or changing its quantity can lead to the death of Gram-negative bacteria. As LpxC is a metal-enzyme, most inhibitors available currently contain a hydroxamic acid group, an zinc binding essential but pharmacokinetic problem group, which can be glucuronidated, sulfated to an inactive form or hydrolyzed to the toxin hydroxylamine..Our preliminary study showed that when the hydroxamic acid in CHIR090 was replaced with other zinc binding groups such as phosphoric acid, borate, silicate, and trifluoroacetyl group, the new compounds remain active against Gram-negative bacteria. It is expected to eliminate its potential metabolic toxicity by these replacement. In the project, the hydroxamic acid group in ACHN975, a compound withdrawn from phase I clinical trials due to inflammation at the infusion site, will be replace with novel zinc binding groups to eliminate its potential metabolic toxicity. After the evaluation of their inhibiting effect, the best zinc binding group was selected and the optimization of the hydrophobic segment in ACHN975 will be conducted. A combination of molecular docking and activity tests will be used for the seeking of novel and broad-spectrum anti-Gram-negative bacteria compound. Finally, the causes of injection inflammation by ACHN975 will be investigated and the similar effect (may existed) of newly obtained inhibitors will be eliminated by using a prodrug strategy.

随着耐药菌的大量出现，感染问题尤其是耐药革兰阴性菌感染，再次成为严重危害人类健康的重要疾病。LpxC是革兰阴性菌外膜脂质A合成过程中的一种关键酶，抑制该酶的功能或者改变其含量都能引起阴性菌的死亡。由于LpxC是一种金属酶，大部分抑制剂均含有锌离子螯合的异羟肟酸基团，容易被代谢失活和水解为毒性的羟胺。.本课题组研究表明，用磷酸基、硼酸基、硅酸基和三氟乙酰基等锌离子螯合基团替换CHIR090中的异羟肟酸，其抗菌活性保持，有望消除其潜在代谢毒性。本项目拟从曾进入I期临床的ACHN975出发，采用前期发现的新型的锌离子络合基团对异羟肟酸基团替换，考察其抗革兰阴性菌活性并确证作用机制；选择活性最好的锌离子络合基团，结合分子对接和活性测试对疏水区优化，开展新型LpxC抑制剂抗革兰阴性菌的构效关系研究；最后考察ACHN975注射刺激产生的原因，并通过前药化消除所得新化合物可能存在的类似刺激性。

随着耐药菌大量出现，感染问题尤其是耐药革兰阴性菌引起的感染，再一次成为严重危害人类健康的重要疾病。革兰阴性菌致病和耐药的重要原因是其表面存在一层阻碍药物进入其内部的外膜。LpxC是细菌合成外膜脂质A过程中的关键酶，其功能异常会导致细菌死亡。目前临床上没有针对该靶标的上市药物，因此不存在潜在的耐药性。因此，开发新型的LpxC抑制剂具有重要意义。.本项目从曾经进入I期临床的候选物ACHN-975出发，尝试用磷酸基、硼酸基、硅酸基和三氟乙酰基等锌离子螯合基团替换替换其异羟肟酸基团，并对其疏水区进行结构优化，开展新型LpxC抑制剂抗革兰阴性菌的构效关系研究。项目研究得到1个候选物，并对其制备工艺进行了2轮优化，使收率提高了10倍；完成了候选物体外及小鼠体内的抗菌活性以及急性毒性研究，结果表明其毒性较低（静脉给药LD50值为161.59 mg/kg）且对于绝大部分菌株活性均优于对照药ACHN-975和粘菌素。.目前项目研究成果已与石家庄以岭药业股份有限公司签订合作开发协议，共同进行该候选物的后续研究。成果转化直接经济效益人民币1亿元；候选化合物具有进一步开发成为1.1类耐药革兰阴性菌感染治疗药物的潜力，具有潜在的社会效益和经济价值。