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.
Highlights
The World Health Organization [1] has highlighted antimicrobial resistance as a major global health concern [1]
We have shown that mitochondria in the cerebrum and sciatic nerve tissues showed abnormal ultrastructure and functions when mice were intravenously injected with colistin at 15 mg/kg/day for 7 days [131,139]
The activation of Akt caused by nerve growth factor (NGF) stimulation significantly attenuated colistin‐induced apoptotic death and the inhibition of axon growth in N2a and PC12 neuronal cells, which involved the activation of nuclear factor erythroid 2-related factor 2 (Nrf2)/ARE
Summary
The World Health Organization [1] has highlighted antimicrobial resistance as a major global health concern [1]. As no new classes of antibiotics will be available for Gram-negative ‘superbugs’ in the near future, we have to develop novel polymyxin combination therapies [2]. Only increasing the dose of polymyxins to overcome resistance isshowed not an that thedue ratestooftoxic nephrotoxicity occurred in approximately after patients received colistin or option side effects Trials have shown that effects these combinations havegrowth no increased benefits compared to their respective confirmed synergistic against bacterial in vitro. TheRecent that combining polymyxins with over curcumin has have been sourcestudies of mosthave of ourshown antibacterial armamentarium and efforts the last 30 many years pharmacological and toxicological benefits monotherapy with eachwith compound per sehas including:. In combination polymyxins hold great for understanding of the underlying molecular mechanisms on nephroand neuroprotection and synergistic infections caused by MDR Gram‐negative pathogens. Understanding of growth the underlying molecular mechanisms on nephro‐ and neuroprotection and synergistic effects on bacterial growth of this novel combination
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