基于结构多样性罗丹明染料库的抗耐药菌活性先导筛选发现及性质改造

Increasing antimicrobial resistance is a public health emergency that warrants coordinated global efforts. Numerous major international and national policies aimed at accelerating the research and development of antibiotics with novel scaffolds have been introduced. Challenge is that no alternative molecular platform has been identified for discovery of abundant antimicrobial hit compounds. In our previous work, a rhodamine library exhibiting facile functional, topographical and stereochemical diversity has been proven as a novel and feasible chemical space for antibacterial compounds screening, yielding two potent wide-spectrum antimicrobial hit compounds with low inducible resistance against resistant pathogens. The high binding affinity with human serum albumin (HSA) lowered the in vivo antibacterial activity. This project intends to overcome this obstacle by utilizing molecular modification strategies, such as surface charge manipulation, target-activatable prodrug and host-guest supramolecular complex construction, aiming to reduce the drug-HAS binding and strength the in vivo antibacterial activity. The implementation of this project will promote the development of rhodamine-type antibacterial molecules, which have great potential in combating antimicrobial resistance. Meanwhile, developing new antibacterial agents from synthetic dyes library is expected to be an innovative research direction for fine organic chemicals.

细菌耐药性是亟待解决的全球性的重大公共卫生安全问题。世界卫生组织和各国政府均推出相关政策与举措，促进全新抗菌药物的研发。新结构抗菌母核的发现是当前抗生素开发领域的研究前沿和难点。申请人在前期研究中发现，结构多样性罗丹明染料实体库是筛选发现高活性抗耐药菌化合物的全新化学空间。两个优选活性化合物具有优异的体外抗菌活性，抗菌谱广、杀菌快速且不易产生诱导耐药。其与血清蛋白有较高的亲和性，抑制了其体内抗菌活性。本项目拟利用表面电荷调控、靶向前药以及主客体化学等理性分子改造策略，来突破该研究瓶颈，促进其活体抗菌疗效的发挥。本项目的开展将有助于推动罗丹明类抗菌活性分子的药物开发，对于耐药菌的治疗有潜在重要应用价值。同时，基于染料的抗菌药物开发也有望成为精细有机化工领域的创新研究方向。

由于抗生素在临床和养殖业的滥用和无序排放，具有多重耐药机制的超级细菌不断涌现，细菌耐药性已成为亟待解决的全球性重大公共卫生安全问题。近五十年获批的抗菌药大多为已有抗生素母核的结构衍生物，细菌快速进化出相应的耐药机制。因此，新结构抗菌母核的发现是当前抗生素开发领域的研究前沿和难点。申请人在前期研究中发现，结构多样性罗丹明染料实体库是筛选发现高活性抗耐药菌化合物的全新化学空间，其中两个优选活性化合物具有优异的体外抗菌活性，抗菌谱广、杀菌快速且不易产生诱导耐药。但其与血清蛋白有较高的亲和性，抑制了其体内抗菌活性。本项目利用表面电荷调控和靶向前药设计的分子改造策略来突破该瓶颈，促进其活体抗菌疗效的发挥。项目首先利用分子表面电荷调控策略对两个优选化合物进行结构改造，构建了系列电正性、电中性、电负性衍生物，通过构效关系研究明确了分子表面正电荷对维持其抗菌活性至关重要。随后针对细菌感染病灶活性氧爆发的特点，设计全新的活性氧激活分子策略，构建系列活性氧激活抗菌前药。活性氧诱导电负性前药分子发生电荷反转，增强前药有效体内循环，实现抗菌活性分子在感染病灶的靶向激活与富集，在小鼠腹腔及皮肤感染活体模型中发挥明显的抗感染治疗效果。本项目的开展将有助于推动罗丹明类抗菌活性分子的药物开发，对耐药菌的治疗有潜在重要应用价值。项目取得了一系列有影响力的研究成果，申请人以第一/通讯作者发表SCI论文14篇，包括J. Am. Chem. Soc. (1篇), CCS Chem. (1篇), Free Radical Biol. Med. (1篇), Sci. China Chem. (1篇), Sens. Actua. Chem. B (3篇)等。授权中国发明专利2项。

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