多重耐药革兰氏阴性菌已成为临床抗感染治疗失败的重要原因之一。基于“Trojan horse”策略设计的铁载体-抗生素偶联物具自由穿越革兰氏阴性菌细胞屏障的特点，有望成为临床医生抗感染疾病治疗的利器。然而Linker的靶向性断裂一直是此类药物面临的关键科学问题，设计一类可在细菌内部选择性释放的特异性Linker对此类药物研发的意义重大。本项目以细菌感染过程中对细胞壁合成发挥重要作用的转肽酶为出发点，充分利用转肽酶所催化底物的特点，创新性的将含转肽酶识别位点的肽段构建到所设计Linker中，旨在克服革兰氏阴性菌由于外膜屏障产生的耐药性。已合成4个目标化合物，其中YZH-001的抗菌活性较原型药物Amoxicillin对E. coli ATCC 25922的活性提高约110倍。下一步，我们将对化合物进行系统的设计并丰富耐药菌株的类型，为发现新型高靶向性、低毒性的抗耐药菌药物提供新的思路。

Multi-drug resistant infections caused by Gram-negative bacteria have became one of the most important reasons for the failure of clinical anti-infective treatment. The siderophore-antibiotic conjugates, which were designed based on the “Trojan horse” strategy and have the features freely through the Gram-negative cell wall, were expected to be a weapon for anti-infection treatment in clinical. However, selective release of the linker is a key problem faced by these compounds, and design a site-specific linker that selective release inside of the bacteria is an essential point of the drug design. In this project, to overcome the resistance of gram-negative bacteria due to the adventitial barrier, we incorporate the recognition site of transpeptidase enzyme into linker innovatively, based on the transpeptidase enzyme that shows an important role in the process of bacterial infections and study the characteristics of the transpeptidase enzyme-catalyzed substrate. In addition. Four compounds have been synthesized and YZH-001 shows an increased 110-fold activities against E. coli ATCC 25922 compared with the parent drug amoxicillin. In the next step, we will do further studies on this new structure and enrich the type of resistant strains, providing a new strategy for discovery of potent highly selective and lower toxic drugs against resistant bacterias.