Matrine Restores Colistin Efficacy Against mcr-1-Carrying Escherichia coli.

The emergence of mcr-1-mediated colistin resistance has become a critical global health concern, highlighting the urgent need for innovative approaches to restore colistin's therapeutic potential. In this study, we evaluated the antibacterial activity of four matrine-type alkaloids-namely, matrine, oxymatrine, sophocarpine, and sophoramine-against mcr-1-positive Escherichia coli. While these alkaloids showed limited efficacy when used alone, the combination of matrine with colistin exhibited remarkable synergistic effects, as demonstrated by checkerboard assays and time-kill curve analyses. The matrine-colistin combination caused minimal erythrocyte damage while effectively attenuating resistance development in vitro. This synergy was further corroborated in a murine infection model, where the combination significantly reduced bacterial loads in target tissues. Mechanistic studies revealed that the matrine-colistin combination enhances antimicrobial activity by disrupting bacterial membrane integrity, increasing intracellular colistin accumulation, and triggering reactive oxygen species-mediated oxidative damage. Collectively, these findings highlight the potential of matrine as a promising adjuvant to overcome colistin resistance, providing a novel therapeutic approach to address the challenge of infections cause by multidrug-resistant Gram-negative bacteria.