Recent emergence of high-level tigecycline resistance mediated by Tet(X3/X4) in Enterobacteriaceae undoubtably constitutes a serious threat for public health worldwide. Antibiotic adjuvant strategy makes antibiotic more effective against these resistant pathogens through interfering intrinsic resistance mechanisms or enhancing antibiotic actions. Herein, we screened a collection of drugs to identify compounds that are able to restore tigecycline activity against resistant pathogens. Encouragingly, we discovered that anti-HIV agent azidothymidine dramatically potentiates tigecycline activity against clinically resistant bacteria. Meanwhile, addition of azidothymidine prevents the evolution of tigecycline resistance in E. coli and the naturally occurring horizontal transfer of tet(X4). Evidence demonstrated that azidothymidine specifically inhibits DNA synthesis and suppresses resistance enzyme activity. Moreover, in in vivo infection models by Tet(X4)-expression E. coli, the combination of azidothymidine and tigecycline achieved remarkable treatment benefits including increased survival and decreased bacterial burden. These findings provide an effective regimen to treat infections caused by tigecycline-resistant Escherichia coli.

Tet（X3 / X4）介导的肠杆菌科中高水平的替加环素耐药性的近期出现无疑对全世界的公共卫生构成了严重威胁。抗生素佐剂策略可通过干扰内在的耐药机制或增强抗生素作用，使抗生素对这些耐药病原体更有效。本文中，我们筛选了一组药物，以鉴定能够恢复替加环素抗药性病原体活性的化合物。令人鼓舞的是，我们发现抗HIV药物叠氮胸苷可显着增强替加环素对临床耐药细菌的活性。同时，添加叠氮胸苷可防止大肠杆菌中对替加环素的抗药性和自然发生的tet水平转移（X4）。有证据表明叠氮胸苷可特异性抑制DNA合成并抑制抗性酶活性。而且，在通过表达Tet（X4）的大肠杆菌进行的体内感染模型中，叠氮胸苷和替加环素的组合获得了显着的治疗益处，包括增加生存率和减少细菌负担。这些发现为治疗由替加环素耐药的大肠杆菌引起的感染提供了有效的方案。