The emergence and spread of the mobile colistin-resistance gene mcr-1 pose a challenge to the use of colistin, a last-resort antibiotic used to treat severe infections caused by extensively drug-resistant (XDR) Gram-negative pathogens. Antibiotic adjuvants are a promising strategy to enhance the efficacy of colistin against colistin-resistant pathogens. Chelerythrine, derived from the traditional Chinese medicine plant Macleaya cordata, exhibits dual inhibitory effects on mobile colistin resistance by impairing the function of mcr-1 and limiting the dissemination of mcr-1-carrying plasmids. A detailed analysis reveals that chelerythrine binds to phospholipids on bacterial membranes and increases cytoplasmic membrane fluidity, thereby impairing respiration, disrupting the proton motive force, generating reactive oxygen species, and decreasing intracellular ATP levels, which subsequently downregulates mcr-1 and conjugation-associated genes. These dual effects of chelerythrine can expand its use of antibiotic adjuvants and may provide a new strategy for circumventing mobile colistin resistance. (This image was conceived by Dr. Lu Yang from Shanghai University of Sport and Ms. Yunrui Tian from China Agricultural University.)
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