Polymyxins–Curcumin Combination Antimicrobial Therapy: Safety Implications and Efficacy for Infection Treatment

Abstract

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.

Polypeptide Self-Assembled Nanoparticles as Delivery Systems for Polymyxins B and E

“…This practice has led to the emergence of negative side-effects, such as neuro-, hepato- and nephrotoxicity [ 7 , 8 ]. Currently, the nephrotoxicity is the major factor limiting the wide applications of polymyxins in clinical practice [ 9 , 10 ]. The development of novel and less toxic antibiotics toward the end of 20th century favored the progressive abandonment of polymyxins as therapeutics.…”

Antimicrobial Mechanisms and Clinical Application Prospects of Antimicrobial Peptides

“…Polymyxin is an antibacterial polypeptide found in the culture medium of Paenibacillus polymyxa. It also targets the cell membrane to exert an antibacterial effect and has a killing effect on most Gram-negative bacilli, including antibiotic-resistant P. aeruginosa and Acinetobacter [226]. It can be applied locally or systemically.…”

The Natural Product Curcumin as an Antibacterial Agent: Current Achievements and Problems

“…In addition, this synergistic effect could be attributed to the inhibitory effect of curcumin on the activities of efflux pumps [9,24]. Curcumin and polymyxin combination treatment for bacterial infections may have another advantage, i.e., significant improvement in the therapeutic index of polymyxins by additionally inhibiting polymyxin-induced cytotoxicity, neurotoxicity, and nephrotoxicity, which is beyond antibacterial activity [93]. This combination may have a powerful application in clinical practice and warrants clinical trials.…”