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Abstract The increasing incidence of bacterial infections caused by multidrug-resistant (MDR) Gram-negative bacteria has deepened the need for new effective treatments. Antibiotic adjuvant strategy is a more effective and economical approach to expand the lifespan of currently used antibiotics. Herein, we uncover that alcohol-abuse drug disulfiram (DSF) and derivatives thereof are potent antibiotic adjuvants, which dramatically potentiate the antibacterial activity of carbapenems and colistin against New Delhi metallo-β-lactamase (NDM)- and mobilized colistin resistance (MCR)-expressing Gram-negative pathogens, respectively. Mechanistic studies indicate that DSF improves meropenem efficacy by specifically inhibiting NDM activity. Moreover, the robust potentiation of DSF to colistin is due to its ability to exacerbate the membrane-damaging effects of colistin and disrupt bacterial metabolism. Notably, the passage and conjugation assays reveal that DSF minimizes the evolution and spread of meropenem and colistin resistance in clinical pathogens. Finally, their synergistic efficacy in animal models was evaluated and DSF-colistin/meropenem combination could effectively treat MDR bacterial infections in vivo. Taken together, our works demonstrate that DSF and its derivatives are versatile and potent colistin and carbapenems adjuvants, opening a new horizon for the treatment of difficult-to-treat infections.

Abstract The emergence and prevalence of mobile colistin resistance gene mcr have dramatically compromised the clinical efficacy of colistin, a cyclopeptide antibiotic considered to be the last option for treating different‐to‐treat infections. The combination strategy provides a productive and cost‐effective strategy to expand the lifespan of existing antibiotics. Structural‐activity relationship analysis of polymyxins indicates that the fatty acyl chain plays an indispensable role in their antibacterial activity. Herein, it is revealed that three saturated fatty acids (SFAs), especially sodium caprate (SC), substantially potentiate the antibacterial activity of colistin against mcr‐positive bacteria. The combination of SFAs and colistin effectively inhibits biofilm formation and eliminates matured biofilms, and is capable of preventing the emergence and spread of mobile colistin resistance. Mechanistically, the addition of SFAs reduces lipopolysaccharide (LPS) modification by simultaneously promoting LPS biosynthesis and inhibiting the activity of MCR enzyme, enhance bacterial membrane damage, and impair the proton motive force‐dependent efflux pump, thereby boosting the action of colistin. In three animal models of infection by mcr‐positive pathogens, SC combined with colistin exhibit an excellent therapeutic effect. These findings indicate the therapeutic potential of SFAs as novel antibiotic adjuvants for the treatment of infections caused by multidrug‐resistant bacteria in combination with colistin.

Summary: Although meropenem, colistin, and tigecycline are recognized as the last-line antibiotics for multidrug-resistant Gram-negative bacteria (MDR-GN), the emergence of mobile resistance genes such as blaNDM, mcr, and tet(X) severely compromises their clinical effectiveness. Developing novel antibiotic adjuvants to restore the effectiveness of existing antibiotics provides a feasible approach to address this issue. Herein, we discover that a Food and Drug Administration (FDA)-approved drug daunorubicin (DNR) drastically potentiates the activity of last-resort antibiotics against MDR-GN pathogens and biofilm-producing bacteria. Furthermore, DNR effectively inhibits the evolution and spread of colistin and tigecycline resistance. Mechanistically, DNR and colistin combination exacerbates membrane disruption, induces DNA damage and the massive production of reactive oxygen species (ROS), ultimately leading to bacterial cell death. Importantly, DNR restores the effectiveness of colistin in Galleria mellonella and murine models of infection. Collectively, our findings provide a potential drug combination strategy for treating severe infections elicited by Gram-negative superbugs.