金属β-内酰胺酶（MBLs）的产生是鲍曼不动杆菌对亚胺培南耐药的重要原因，目前临床上尚无有效的耐药逆转策略。我们前期经构效优化合成了以新型抗菌聚合物—胍基功能化聚碳酸酯为核心，能够在体内自组装形成具有核壳结构的可降解阳离子自组装体L/D2。前期研究发现，L/D2能高效杀伤产MBLs鲍曼不动杆菌并逆转其对亚胺培南耐药，但具体作用机制不明。初步机制研究提示L/D2能与金属辅酶Zn2+竞争性结合MBLs。据此我们提出科学假说：L/D2与Zn2+竞争性结合MBLs酶活性位点是其逆转产MBLs鲍曼不动杆菌对亚胺培南耐药的重要机制。本项目拟从分子、细菌及动物水平明确L/D2能有效逆转产MBLs鲍曼不动杆菌对亚胺培南耐药并评估其生物安全性；利用酶蛋白纯化、等离子体质谱、微量热涌动等技术阐明L/D2与MBLs的具体相互作用。本研究成果对阐明该类共聚物的抗菌机制具有重要的理论意义，具有潜在的临床应用价值。

The production of metal β-lactamase (MBLs) is an important mechanism for the resistance of Acinetobacter baumannii to imipenem, which still lacks effective strategy of drug resistance reversal. By means of optimizing structure-activity relationships, a novel biodegradable triblock copolymer of PEG, guanidinium-functionalized polycarbonate and polylactide is synthesized as antibacterial agent, which self-assemble in vivo to form a degradable cationic micellar nanoparticles (L/D2) with a core-shell structure. Preliminary experiments showed that L/D2 was highly effective against MBLs-producing Acinetobacter baumannii, and reversed its resistance to imipenem. However, the specific mechanism was unknown. We found that L/D2 could compete with zinc ions to bind with MBLs. Hence, we proposed a scientific hypothesis that competitively binding between L/D2 and MBLs is an crucial mechanism to reverse resistance of MBLs-producing Acinetobacter baumannii to imipenem. The project intends to determine L/D2 could effectively reverse the resistance of MBLs-producing Acinetobacter baumannii to imipenem at molecular, cellular and animal level. By using the enzyme protein purification, plasma mass spectrometry (ICP-MS), microscale thermophoresis (MST) and other technologies, we intend to clarify the specific interaction between L/D2 and MBLs and evaluate its biological safety. The results of this research are of great theoretical significance to clarify the antibacterial mechanism of this polymer and provide experimental evidence for possible clinical applications.