抗耐药菌吡唑母核Pyrrolomycin类似物的优化和机制研究

The emergence of highly pathogenic drug-resistant bacteria has become major issues for public health and safety. In recent years, as one of the main causes of bacterial drug resistance, bacterial biofilm becomes a hot topic for drug researches. Pyrrolomycin, as a class of natural products isolated from marine organisms, have been confirmed with good anti-Gram-positive bacterial property and good anti-bacterial biofilm activity. Anyway, these compounds and synthetic analogues were failed to be promoted to drug candidates due to their toxicity and synthetic difficulties. Furthermore, the studies on anti-drug-resistant bacterial activity and the relevant mechanism are also insufficient. After a rational design and synthetic methodology research, a series of pyrrolomycin analogues with pyrazole scaffold were synthesized. The compound YCH1706, with improved metabolic stability and better toxicity, showed a hundred times better anti-bacterial activity than Vancomycin for Gram-positive Vancomycin-resistant Enterococcus faecalis, Methicillin-resistant Staphylococcus aureus and Methicillin/linezolid-resistant Staphylococcus aureus. YCH1706 displayed excellent anti-drug-resistant bacterial activity and a great research prospect. This compound will be further modified to improve its anti-drug-resistant bacterial activity and metabolism stability, reducing its toxicity and binding rate of plasma. This application aims to find the leading compound for anti-drug-resistant Gram-positive bacterial with full independent intellectual property, and also, try to understand the related mechanism of anti-bacterial biofilm.

耐药致病菌的出现已成为重大公共卫生安全问题。近年，作为细菌耐药主要原因之一的细菌生物膜成为研究热点。Pyrrolomycin是一类分离于海洋生物的天然产物，其被证实具有较好的抗革兰氏阳性菌和抗细菌生物膜活性。但该类天然产物及现有合成类似物因为毒性、合成困难等原因无法推进成药性研究，并缺乏抗耐药菌活性和作用机制研究。经过合理结构设计和合成方法学研究，我们合成了一类吡唑母核pyrrolomycin类似物。其中，化合物Y1706对临床较常见万古霉素耐药的粪肠球菌、耐甲氧西林金葡菌、耐甲氧西林及利奈唑胺的金葡菌等革兰氏阳性耐药菌的活性均优于万古霉素百倍以上，并优化了化合物毒性和代谢稳定性，体现出良好的的研究前景。下步工作将通过对结构的修饰，进一步提高化合物的抗耐药菌活性和成药性，降低血浆蛋白结合率，以期得到具有完全自主知识产权的抗革兰氏阳性耐药菌的先导化合物，并进行相关的抗耐药机制研究。

本项目以海洋天然产物Pyrrolomycin类似物Y1706为苗头化合物，为提高化合物对耐药革兰氏阳性菌的抑制活性和成药性，设计合成了吸电子取代吡咯/吡唑（73个）、色酮/硫代色酮并吡唑（15个）、色酮并噻唑（43个）三大类Pyrrolomycin类似化合物。该三类母核的合成方法及活性研究均未有报道。在对化合物进行抗耐药革兰氏阳性菌抑制活性评价实验后，得到了2个对多种耐药革兰氏阳性菌均具有很强抑制活性的化合物，其活性优于万古霉素数十倍。进一步的机制实验研究表明其抗菌及抗耐药机制与抑制细菌生物膜生成相关，具有很好的研究价值和应用前景。先导化合物的代谢性质评价基本完成，体内活性验证研究正在推进之中。此外，第三类色酮并噻唑类化合物虽然抗菌活性不佳，但该类化合物具有较强的抑制细胞因子IL-1β的分泌活性，并且有较好的安全性，对多种炎症相关的疾病，如肿瘤、骨关节炎、自身免疫性疾病等有潜在的治疗作用，具有理想的临床应用前景，值得进一步研究。

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