Characterization of substituted piperazines able to reverse MDR in Escherichia coli strains overexpressing resistance-nodulation-cell division (RND) efflux pumps
Year: 2022
Authors: Casalone E., Vignolini T., Braconi L., Gardini L., Capitanio M., Pavone FS., Giovannelli L., Dei S., Teodori E.
Autors Affiliation: Univ Florence, Dept Biol, Via Madonna Piano 6, I-50019 Sesto Fiorentino, Italy; LENS European Lab Nonlinear Spect, Via Nello Carrara 1, I-50019 Sesto Fiorentino, Italy; Dept Neurosci Psychol Drug Res & Childs Hlth, Sect Pharmaceut & Nutraceut Sci, Via U Schiff 6, I-50019 Sesto Fiorentino, Italy; CNR, Natl Inst Opt, Largo Fermi 6, I-50125 Florence, Italy; Univ Florence, Dept Phys & Astron, Via Sansone 1, I-50019 Sesto Fiorentino, Italy; Univ Florence, Dept Neurosci Psychol Drug Res & Childs Hlth, Sect Pharmacol, Viale Pieraccini 6, I-50139 Florence, Italy.
Abstract: Background MDR in bacteria is threatening to public health. Overexpression of efflux pumps is an important cause of MDR. The co-administration of antimicrobial drugs and efflux pump inhibitors (EPIs) is a promising approach to address the problem of MDR. Objectives To identify new putative EPIs and to characterize their mechanisms of action. Methods The effects of four selected piperazine derivatives on resistance-nodulation-cell division (RND) pumps was evaluated in Escherichia coli strains overexpressing or not expressing RND pumps by assays aimed at evaluating antibiotic potentiation, membrane functionality, ethidium bromide accumulation and AcrB expression. The cytotoxicity of selected piperazines towards primary cultures of human dermal fibroblasts was also investigated. Results Four molecules enhanced levofloxacin activity against strains overexpressing RND efflux pumps (AcrAB-TolC and AcrEF-TolC), but not against RND pump-deficient strains. They had little effects on membrane potential. Molecule 4 decreased, whereas the other three increased, membrane permeability compared with untreated control cells. The four molecules showed differences in the specificity of interaction with RND efflux pumps, by inactivating the transport of one or more antibiotics, and in the levels of ethidium bromide accumulation and of acrB expression inhibition. Conclusions Piperazine derivatives are good candidates as inhibitors of RND efflux pumps. They decreased the activity of RND pumps by mixed mechanisms of action. Small structural differences among the molecules can be critical in defining their behaviour.
Journal/Review: JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
Volume: 77 (2) Pages from: 413 to: 424
More Information: This work was supported by the European Union’s Horizon 2020 research and innovation programme grant no. 871124 Laserlab-Europe and by EMPIR project MetVBadBugs 15HLT01.KeyWords: Antimicrobial Drug Susceptibility; Multidrug-resistance; Pseudomonas-aeruginosa; Salmonella-enterica; Biological-activity; In-vitro; Derivatives; Inhibitors; Acrb; 1-(1-naphthylmethyl)-piperazineDOI: 10.1093/jac/dkab388ImpactFactor: 5.200Citations: 6data from “WEB OF SCIENCE” (of Thomson Reuters) are update at: 2024-11-03References taken from IsiWeb of Knowledge: (subscribers only)Connecting to view paper tab on IsiWeb: Click hereConnecting to view citations from IsiWeb: Click here
