Equisetin Restores Colistin Sensitivity against Multi-Drug Resistant Gram-Negative Bacteria

• Main Authors: Qi Zhang (Author), Shang Chen (Author), Xiaojia Liu (Author), Wenhan Lin (Author), Kui Zhu (Author)
• Format: Book
• Published: MDPI AG, 2021-10-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antibiotics10101263; 2079-6382
• Keywords: equisetin; colistin; Gram-negative bacteria; drug combination; antimicrobial resistance; Therapeutics. Pharmacology; RM1-950
• Source: Antibiotics, Vol 10, Iss 10, p 1263 (2021)

The overuse of antibiotics and the scarcity of new drugs have led to a serious antimicrobial resistance crisis, especially for multi-drug resistant (MDR) Gram-negative bacteria. In the present study, we investigated the antimicrobial activity of a marine antibiotic equisetin in combination with colistin against Gram-negative bacteria and explored the mechanisms of synergistic activity. We tested the synergistic effect of equisetin in combination with colistin on 23 clinical <i>mcr-1</i> positive isolates and found that 4 µg/mL equisetin combined with 1 µg/mL colistin showed 100% inhibition. Consistently, equisetin restored the sensitivity of 10 species of <i>mcr-1</i> positive Gram-negative bacteria to colistin. The combination of equisetin and colistin quickly killed 99.9% bacteria in one hour in time-kill assays. We found that colistin promoted intracellular accumulation of equisetin in colistin-resistant <i>E. coli</i> based on LC-MS/MS analysis. Interestingly, equisetin boosted ROS accumulation in <i>E. coli</i> in the presence of colistin. Moreover, we found that equisetin and colistin lost the synergistic effect in two LPS-deficient <i>A. baumannii</i> strains. These findings suggest that colistin destroys the hydrophobic barrier of Gram-negative bacteria, facilitating equisetin to enter the cell and exert its antibacterial effect. Lastly, equisetin restored the activity of colistin in a <i>G. mellonella</i> larvae infection model. Collectively, these results reveal that equisetin can potentiate colistin activity against MDR Gram-negative bacteria including colistin-resistant strains, providing an alternative approach to address Gram-negative pathogens associated with infections in clinics.