AUTHOR=Cannatelli Antonio , Principato Silvia , Colavecchio Olga L. , Pallecchi Lucia , Rossolini Gian Maria 

TITLE=Synergistic Activity of Colistin in Combination With Resveratrol Against Colistin-Resistant Gram-Negative Pathogens

JOURNAL=Frontiers in Microbiology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2018.01808

DOI=10.3389/fmicb.2018.01808

ISSN=1664-302X

ABSTRACT=<p><bold>Objectives:</bold> 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.</p><p><bold>Methods:</bold> 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 (<italic>Klebsiella pneumoniae, n</italic> = 6, <italic>Escherichia coli, n</italic> = 6; <italic>Citrobacter braakii, n</italic> = 1; <italic>Stenotrophomonas malthophilia, n</italic> = 1; <italic>Enterobacter cloaceae, n</italic> = 1<italic>; Acinetobacter baumannii, n</italic> = 1) with acquired colistin resistance, three colistin-susceptible <italic>K. pneumoniae</italic> precursors, and two strains of intrinsically colistin-resistant species (<italic>Serratia marcescens, n</italic> = 1; <italic>Proteus mirabilis, n</italic> = 1). Mechanisms of acquired colistin resistance included chromosomal mutations (i.e., <italic>mgrB, pmrAB</italic>) and plasmid genes (<italic>mcr-1, mcr-1</italic>.2).</p><p><bold>Results:</bold> 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 <italic>K. pneumoniae</italic> strains, and for two <italic>mcr-1</italic>-positive <italic>E. coli</italic> 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.</p><p><bold>Conclusions:</bold> 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.</p>