Abstract
Objective: The aim of this study was to determine if the plant phenolic curcumin (CUR) and the arylpiperazine 1-(1-naphthylmethyl)-piperazine (NMP) could restore antibiotic efficacy versus MDR P. aeruginosa infection. Methods: The MICs of piperacillin, meropenem and levofloxacin in the presence or absence of CUR or NMP against a MDR strain that over-expresses the MexAB-OprM efflux-pump and the isogenic parent strain were compared. The efficacy of the same combination treatments was also tested in a Galleria mellonella in vivo infection model and larval survival and bacterial burden compared. Results: In vitro, CUR restored the activity of piperacillin, meropenem and levofloxacin versus the MDR strain of P. aeruginosa only weakly. There was no evidence in vitro of a similar effect with NMP. In vivo, treatment of G. mellonella larvae infected with the MDR strain with a combination of NMP or CUR plus levofloxacin, and piperacillin plus CUR, resulted in enhanced therapeutic benefit compared to the monotherapies. When compared with monotherapies, the enhanced efficacy of the combination treatments correlated with reduced bacterial burden.Conclusion: CUR and NMP restored the efficacy of antibiotic therapy in vivo versus MDR P. aeruginosa infection.
Highlights
P. aeruginosa is an opportunistic Gram-negative pathogen accounting for significant morbidity and mortality worldwide and is the second most frequent cause of healthcare- or ventilator-associated pneumonia [1]
Mutations in efflux-pump regulatory genes can result in efflux-pump overexpression that confers a Multidrug resistance (MDR) phenotype [3] and are commonly identified in clinical isolates, for example, mutations in nalB result in over-expression of MexAB-OprM, and contribute to reduced clinical efficacy of some antibiotics [4]
These antibiotics were tested because previous work with a broad range of antibiotics revealed that the greatest decreases in susceptibility occurring in the nalB-type strain compared to the parent strain occurred with these drugs [15]
Summary
P. aeruginosa is an opportunistic Gram-negative pathogen accounting for significant morbidity and mortality worldwide and is the second most frequent cause of healthcare- or ventilator-associated pneumonia [1]. P. aeruginosa is likely to pose a major therapeutic challenge in future [1]. Membrane-associated efflux-pumps belonging to the resistancenodulation-division (RND) family actively export antibiotics and as a consequence are major contributors to P. aeruginosa antibiotic resistance [1]. Of the 12-member RND family, MexAB-OprM is considered to be the most important efflux-pump mediating antibiotic resistance in P. aeruginosa because it transports a broad range of antibiotics [1]. Mutations in efflux-pump regulatory genes can result in efflux-pump overexpression that confers a MDR phenotype [3] and are commonly identified in clinical isolates, for example, mutations in nalB result in over-expression of MexAB-OprM, and contribute to reduced clinical efficacy of some antibiotics [4]. Treatments that combine efflux-pump inhibitors (EPIs) with antibiotics that are normally ineffective due to efflux could result in restoration of the normal clinical efficacy of the drug [5]
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