基于微透析和可视化技术的大黄酸抗生物被膜PK/PD研究

The formation of biofilm is one of the most important mechanism of bacterial drug resistance. Since no specific drug was developed for the biofilm control, which is a tremendous challenge for clinic, high-dose antibiotics is still the main treatment presently. The potent bilfilm eradication ability of rhein was found by our group for the first time, and we planed to carry out the combination therapy of rhein with antibiotics on biofilm. Pharmacokinetic/pharmacodynamic (PK/PD) study of antimicrobial is an important strategy to develop rational dosage regimen, improve therapeutic effect, and control drug resistance. In order to obtain more accurate evaluation and provide more rational dosage regimens, this project planed to do certain innovation and modification on the traditional antibacterial PK/PD model to achieve following improvements: ① more accurate research model- animal model of biofilm infection; ② more precise research objects- drug concentration at infection site determinined by microdialysis technology; ③ more efficient research method- real-time bacteria quantification by visualization technology based on bioluminescent. In the present study, we aimed to conduct the anti-biofilm PK/PD study of rhein based on the models mentioned above to clarify its PK/PD characteristics and develop rational dosage regimens. This project will provide a theoretical support for the development of rhein as effective anti-biofilm drugs and material support for the development of natural products, which will greatly enhance our ability on the development of innovative anti-infective natural drug.

生物被膜是细菌耐药的重要机制之一，目前仍以大剂量抗生素为治疗手段，无特异性药物上市，为临床治疗带来巨大挑战。本项目首次发现大黄酸具有强效的生物被膜清除能力，拟开展大黄酸与抗生素联合用药抗生物被膜研究。抗菌药物的药物动力学/药效学（PK/PD）研究，是制定合理给药方案、提高疗效的重要策略。本项目拟通过对传统抗菌PK/PD模型的创新优化，实现①研究模型更准确—生物被膜感染动物模型；②评价对象更精确—微透析技术实现对感染病灶药物浓度的测定；③研究手段更高效—生物发光可视化技术用于细菌的实时快速定量，从而可开展更精准的评价、提供更合理的给药方案。本项目拟在此基础上开展大黄酸联合抗生素抗生物被膜的PK/PD研究，明确其PK/PD特性，制定合理给药方案；为将大黄酸开发为有效清除细菌生物被膜的新药提供理论依据，具有重要的科研价值和社会意义，为我国天然产物在抗感染领域走向世界前沿提供物质保障。

生物被膜是细菌耐药的重要机制之一，目前无特异性药物上市，为临床治疗带来巨大挑战。本项目首次发现并证实大黄酸具有强效抑制生物被膜形成和清除已生成的生物被膜的能力，并初步阐明其抗生物被膜的作用机制可能与抑制细菌群体效应QS有关。成功建立了金黄色葡萄球菌感染的大鼠心内膜炎模型作为评价大黄酸抗细菌生物被膜的动物模型，开展大黄酸与万古霉素联合用药抗生物被膜研究。通过微透析——LC-MS/MS方法，测定了血浆中游离大黄酸的药物浓度，并初步测定了其药代动力学参数。抗菌药物PK/PD研究，是制定合理给药方案、提高疗效的重要策略。通过考察不同的大黄酸的给药方案和PK/PD研究，我们发现T>MIC是与大黄酸抗生物被膜活性相关性最好的PK/PD参数，即大黄酸抗生物被膜是时间依赖性的，多次给药会有更好的清除生物被膜的效果。本课题为大黄酸开发为有效清除细菌生物被膜的新药提供理论依据，具有重要的科研价值和社会意义，为我国天然产物在抗感染领域走向世界前沿提供物质保障。