Polymyxins–curcumin combination antimicrobial therapy: Safety implications and efficacy for infection treatment

The emergence of antimicrobial resistance in Gram‐negative bacteria poses a huge health challenge. The therapeutic use of polymyxins (i.e., colistin and polymyxin B) is commonplace due to high efficacy and limiting treatment options for multidrug‐resistant Gram‐negative bacterial infections. Nephrotoxicity and neurotoxicity are the major dose‐limiting factors that limit the therapeutic window of polymyxins; nephrotoxicity is a complication in up to ~60% of patients. The emergence of polymyxin‐resistant strains or polymyxin heteroresistance is also a limiting factor. These caveats have catalyzed the search for polymyxin combinations that synergistically kill polymyxin‐susceptible and resistant organisms and/or minimize the unwanted side effects. Curcumin—an FDA‐approved natural product—exerts many pharmacological activities. Recent studies showed that polymyxins–curcumin combinations showed a synergistically inhibitory effect on the growth of bacteria (e.g., Gram‐positive and Gram‐negative bacteria) in vitro. Moreover, curcumin co‐administration ameliorated colistin‐induced nephrotoxicity and neurotoxicity by inhibiting oxidative stress, mitochondrial dysfunction, inflammation and apoptosis. In this review, we summarize the current knowledge‐base of polymyxins–curcumin combination therapy and discuss the underlying mechanisms. For the clinical translation of this combination to become a reality, further research is required to develop novel polymyxins–curcumin formulations with optimized pharmacokinetics and dosage regimens.