Abstract
Objectives: In this study, we investigated the antimicrobial activity of resveratrol in combination with colistin, a last-resort agent for the treatment of severe infections caused by multidrug resistant Gram-negative pathogens.Methods: The synergistic activity and the bactericidal activity of colistin in combination with resveratrol was investigated by checkerboard assays and time-kill assays, respectively. A total of 21 strains were investigated, including 16 strains of different species (Klebsiella pneumoniae, n = 6, Escherichia coli, n = 6; Citrobacter braakii, n = 1; Stenotrophomonas malthophilia, n = 1; Enterobacter cloaceae, n = 1; Acinetobacter baumannii, n = 1) with acquired colistin resistance, three colistin-susceptible K. pneumoniae precursors, and two strains of intrinsically colistin-resistant species (Serratia marcescens, n = 1; Proteus mirabilis, n = 1). Mechanisms of acquired colistin resistance included chromosomal mutations (i.e., mgrB, pmrAB) and plasmid genes (mcr-1, mcr-1.2).Results: Resveratrol did not show any significant intrinsic antimicrobial activity. Overall, a relevant synergistic antimicrobial activity of resveratrol in combination with colistin was observed with all tested strains, except for the three colistin-susceptible K. pneumoniae strains, and for two mcr-1-positive E. coli strains. In time-kill assays, performed with 15 selected strains, the combination of colistin 2 mg/L plus resveratrol 128 mg/L was bactericidal with 11 strains, and bacteriostatic for the remaining ones.Conclusions: Resveratrol was found to potentiate colistin activity against a wide panel of colistin-resistant strains, regardless of species and resistance mechanisms, which would deserve further investigation for potential clinical applications.
Highlights
Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a stilbenoid compound found in numerous plants
Resveratrol has been investigated for potential therapeutic effects in various diseases (Chen et al, 2005; Albani et al, 2010; Sawda et al, 2010; Sun et al, 2010; Singh et al, 2014; Li et al, 2016, 2017) and has shown the potential for antiviral (Abba et al, 2015; Lin et al, 2017a,b) and antibacterial activity against some pathogens, including Helicobacter pylori, Propionibacterium acnes, and Staphylococcus aureus (Mahady et al, 2003; Su et al, 2014; Taylor et al, 2014)
Due to the emergence of extremely drug resistant (XDR) strains of Gram-negative pathogens, such as carbapenemresistant Enterobacteriaceae (CRE) and carbapenem-resistant Acinetobacter sp. (CRA), polymyxins have regained a major role as last-resort agents for these infections, and their consumption has remarkably increased (Falagas and Kasiakou, 2005; Kaye et al, 2016)
Summary
Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a stilbenoid compound found in numerous plants. Due to the emergence of extremely drug resistant (XDR) strains of Gram-negative pathogens, such as carbapenemresistant Enterobacteriaceae (CRE) and carbapenem-resistant Acinetobacter sp. Polymyxin resistance has emerged and is increasingly reported, especially among CRE and CRA (Cannatelli et al, 2013; Monaco et al, 2014; Granata and Petrosillo, 2017; Jeannot et al, 2017; Nowak et al, 2017), further narrowing the treatment options
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