原创性联合用药防细菌耐药规律在体外生物膜PK/PD模型上的验证完善及可操作性细化研究

抗菌药物抗药性严重威胁着人类健康，联合用药防细菌耐药的有效性被不断证明，然偶有矛盾报道，且尚未形成规律性指导思想。课题组受新型抗菌药物研究的启发，首次发现联合用药的防细菌耐药潜能与其组合比例密切相关等规律，部分已被Nature等期刊论文证明，并获国际学术奖励，且理论上可诠释联合用药报道结果各异的合理性，然而用于指导联合用药的临床实践尚需进一步探究。为此，该课题拟选用前期获知高效防MRSA耐药的组合物罗红/强力霉素为研究对象，采用现代微生物学研究方法和LC-MS技术等，对组合物中药物单用和不同比例组合在体外生物膜模型上防MRSA耐药的多指标药动学/药效学（PK/PD）进行系统研究；同时结合对罗红/强力霉素单用和特定比例组合在相同模型上干预后MRSA蛋白质组的深入研究和有效沟通，验证完善和可操作性细化前期发现的联合用药防细菌耐药规律，为联合用药防细菌耐药策略的临床实践和精准实施打下坚实基础。

Antimicrobial resistance (AMR) has become a serious threat to human health, and the strategy of drug combination to prevent resistance has been constantly proved to be effective. However, there are occasional conflicting reports, and no regularity guiding ideology has yet been presented. Inspired by the research of new antibacterial agents, laws of drug combination, including that the potential of drug combination preventing AMR was close related to the proportional of two antimicrobial agents, were first discovered by us, and some of which are proved by publications on the journals of Nature, etc. and for which we also obtained an international academic award. Theoretically, these can also interpret the rationality of different results of various drug combinations to prevent AMR. However, its clinical practices guiding drug combinations need to be further explored. For this purpose, a combination roxithromycin/doxycycline (RM/DC), with great effects to prevent resistance of methicillin-resistant Staphylococcus aureus (MRSA), was used as the research object, and the multi-index pharmacokinetics/pharmacodynamics (PK/PD) of RM/DC with single use of each drug and different proportions, on in vitro biofilm model, was systematically researched using modern microbiology research methods, HPLC-MS/MS technology, and so on. Combined with the in-depth research and effective communication of MRSA proteome after which was intervened with the combination RM/DC alone and specific proportions on the same model, the law of drug combinations to prevent AMR can be verified and improved, and its operability can be further detailed. This will lay a solid foundation for the clinical practice and precise implementation of the strategy of drug combinations to prevent AMR.