Precise Synthesis of Tri‐Pyrroles for Combating Drug‐Resistant Bacteria

Abstract Drug‐resistant bacterial infections pose a significant challenge to global public health. Therefore, developing theranostic agents with high efficacy, low drug resistance, and excellent biocompatibility for the effective treatment of drug‐resistant bacterial infections is urgently needed. Herein, a series of cationic 3,2′ and 3′,3″‐linked tri‐pyrrole (Tri‐Py) oligomers with yellow fluorescence from readily available N ‐aryl‐3,4‐dihydro‐2,5‐dimethylpyrroles through a one‐pot oxidative coupling reaction is developed. These cationic Tri‐Py oligomers can be easily decorated with various functional groups, enabling modification of antibacterial activity and selectivity against Gram‐positive and Gram‐negative bacteria. Compared with conventional antibiotics, Tri‐Py oligomers can effectively combat drug‐resistant bacteria and their corresponding biofilms by dual disruption of bacterial membrane and DNA, leading to low drug resistance and cross‐resistance. In addition, they demonstrated excellent in vivo antibacterial efficacy and biocompatibility in mouse models of skin wounds and peritonitis induced by drug‐resistant bacteria. As a novel theranostic skeleton, Tri‐Py oligomers show promise for clinical applications in the treatment of drug‐resistant bacterial infections.