抗超广谱耐药摩氏摩根菌先导化合物的构效关系与作用机制研究

Multidrug-resistant (MDR) bacterial infections, especially those caused by Gram-negative pathogens, have emerged as one of the world’s greatest health threats. In our previous study, the lead compounds were found from 100,000 compound libraries in the high-through-screening system against the super-spectrum drug-resistant Morganella morganii KL-225. The lead compound 2 has shown very potent antibacterial activity against multidrug-resistant strains, including NDM-1 Gram-negative pathogens. The anti-MRSA and VRE activity of the lead compound was more active than clinic anti-MRSA agent – Linezolid. The anti-NDM-1 activity was more potent than Meropenem, Faropenem, Levofloxacin and Minocycline; was comparable to that of Tigecycline and slightly less active than that of Colistin. It was found that the lead compound was effective against MRSA infection in vivo and has novel mechanism of action. This research will be focus on structure-activity relationships and novel mechanism of action of lead compound 2 in order to discover more potent and less toxic drug candidate against MDR pathogens, including NDM-1 gram-negative pathogens. This research will be helpful for further rational drug design to discover new antibacterial drugs against MDR pathogens with novel mechanism of action in the future.

多重耐药菌感染，特别是革兰氏阴性耐药菌引起的感染已成为全世界健康的最大威胁之一。前期研究中，我所以超广谱耐药的摩氏摩根菌KL-225为模式生物建立筛选模型，从10万个化合物样品中筛选得到了全新结构的抗菌先导化合物。该化合物体外具有很强的广谱抗耐药菌活性，包括NDM-1超级耐药菌。抗MRSA、VRE活性强于临床上用于治疗MRSA药物利奈唑胺。对NDM-1阴性耐药菌活性强于临床用药美罗培南、左氟沙星、法罗培南、米诺环素，与替加环素相当，稍弱于多粘菌素。在体内抗MRSA动物模型上显示了很好的有效性；并初步证明其具有新的作用机制。本研究通过对先导化合物进行构效关系研究和结构优化，以期获得新型抗耐药菌，特别是抗革兰氏阴性耐药菌的候选药物；并通过先导化合物寻找抗菌药物新靶标，为今后的理性药物设计，发现具有全新结构的新型抗耐药菌药物奠定基础。

多重耐药菌感染，特别是革兰氏阴性耐药菌引起的感染已成为全世界健康的最大威胁之一。前期研究中，我所从超广谱耐药的摩氏摩根菌KL-225筛选模型中筛选得到了全新结构的抗菌先导化合物2。该化合物体外具有很强的广谱抗耐药菌活性，包括NDM-1超级耐药菌。对NDM-1阴性耐药菌活性强于临床用药美罗培南、左氟沙星、法罗培南、米诺环素，与替加环素相当，稍弱于多粘菌素。本研究通过对先导化合物2进行构效关系研究和结构优化，并对其作用机制进行了研究。结果表明，先导化合物2不仅作用于DNA，并同时作用于新的作用靶点十一异戊烯二磷酸合酶（UPPS），该酶是用于合成细菌细胞壁的肽聚醣的必要前体物。同时，获得了新的抗革兰氏阴性耐药菌与阳性耐药菌的候选化合物V-22-1与IV-62-2，进行进一步的成药性评价，为今后的理性药物设计，发现具有全新结构的新型抗耐药菌药物奠定基础。