A New Discovery of Unique 13-(Benzimidazolylmethyl)berberines as Promising Broad-Spectrum Antibacterial Agents

Abstract

A new hybridization of berberine and benzimidazoles was performed to produce 13-(benzimidazolylmethyl)berberines (BMB) as potentially broad-spectrum antibacterial agents with the hope of confronting multidrug-resistant bacterial infections in the livestock industry. Some of the newly prepared hybrids showed obvious antibacterial effects against tested strains. Particularly, 13-((1-octyl-benzimidazolyl)methyl)berberine <b>6f</b> (OBMB-<b>6f</b>) was found to be the most promising compound that not only exerted a strong activity (MIC = 0.25-2 μg/mL) and low cytotoxicity but also possessed a fast bactericidal capacity and low propensity to develop resistance toward <i>Staphylococcus aureus</i> and <i>Escherichia coli</i> even after 26 serial passages. Moreover, OBMB-<b>6f</b> displayed the ability to prevent bacterial biofilm formation at low and high temperatures. The mechanistic exploration revealed that OBMB-<b>6f</b> could significantly disintegrate bacterial membranes, markedly facilitate intracellular ROS generation, and efficiently intercalate into DNA. These results provided a profound insight into BMB against multidrug-resistant bacterial infections in the livestock industry.