As a major public health concern, drug-resistant bacteria are insensitive to commonly used antibiotics. However, few novel antibiotics have been approved since 1960s. Thus, it is an urgent need to develop new classes of antimicrobial compounds that are capable of overcoming acquired resistance. Recently, researchers proposed that bacteria undergoing microptosis may not develop resistance and two classes of immunotherapeitics (antigenic epitopes attached polymyxin B and IspH inhibitors) were discovered.^1,2 Herein, we designed and synthesized a series of novel small molecules through hybriding known antibiotics or marine antimicrobial natural products with IspH inhibitors which can activate T cells and deliver granzymes to within bacteria to induce microptosis. Among them, several compounds displayed broad-spectrum antimicrobial activities against Escherichia coli, Staphylococcus aureus, Bacillus subtilis, etc. Surprisingly, several intermediates exhibited potent killing effects against Pseudomonas aeruginosa with the MIC values of 0.5 μg/mL. Further studies on inducing immune response via flow cytometry are under way.





Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 41830535; 4217060347; 81874300), and the Taishan Scholars Program, China.



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