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.