Restoring the activity of the antibiotic aztreonam using the polyphenol epigallocatechin gallate (EGCG) against multidrug-resistant clinical isolates of Pseudomonas aeruginosa

Betts, Jonathan W., Hornsey, Michael, Higgins, Paul G., Lucassen, Kai, Wille, Julia, Salguero, Francisco, Seifert, Harald and La Ragione, Roberto M. (2019) Restoring the activity of the antibiotic aztreonam using the polyphenol epigallocatechin gallate (EGCG) against multidrug-resistant clinical isolates of Pseudomonas aeruginosa Journal of Medical Microbiology, 68 (10).

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Abstract

Introduction. Pseudomonas aeruginosa is an important Gram-negative pathogen that is intrinsically multidrug-resistant (MDR) and frequently associated with healthcare-associated outbreaks. With increasing resistance to antibiotics and with very few novel drugs under development, clinicians often use combinations to treat critically ill patients.

Aim. The aim of this study was to evaluate the ability of epigallocatechin (EGCG) to restore the activity of aztreonam against clinical MDR strains of P. aeruginosa.

Methodology. Checkerboard and time–kill kinetic assays were performed to assess synergy in vitro and the Galleria mellonella model of infection was used to test the efficacy of the combination in vivo. Accumulation assays were performed to gain insight into the mechanism of action.

Results. The results demonstrate that synergy between aztreonam and EGCG exists [fractional inhibitory concentration indices (FICIs) 0.02-0.5], with the combination affording significantly (P=˂0.05) enhanced bacterial killing, with a ˃3 log10 reduction in colony-forming units ml−1 at 24 h. EGCG was able to restore susceptibility to aztreonam to a level equal to or below the breakpoint set by the European Committee for Antimicrobial Susceptibility Testing. In G. mellonella, the combination was superior to monotherapy, with increased larval survival observed (94 % vs ≤63 %). We also demonstrated the relatively low toxicity of EGCG to human keratinocytes and G. mellonella larvae. Accumulation assay data suggest that the mechanism of synergy may be due to EGCG increasing the uptake of aztreonam.

Conclusion. EGCG was able to restore the activity of aztreonam against MDR P. aeruginosa . The data presented support further evaluation of the aztreonam–EGCG combination and highlight its potential for use in clinical medicine.

Item Type:	Article
Divisions :	Faculty of Health and Medical Sciences > School of Veterinary Medicine
Authors :	Name Email ORCID Betts, Jonathan W. jono.betts@surrey.ac.uk Hornsey, Michael mike.hornsey@surrey.ac.uk Higgins, Paul G. Lucassen, Kai Wille, Julia Salguero, Francisco f.salguerobodes@surrey.ac.uk Seifert, Harald La Ragione, Roberto M. R.Laragione@surrey.ac.uk
Date :	1 October 2019
DOI :	10.1099/jmm.0.001060
Copyright Disclaimer :	© Jonathan W. Betts; Michael Hornsey; Paul G. Higgins; Kai Lucassen; Julia Wille; Francisco J. Salguero; Harald Seifert; Roberto M. La Ragione. The definitive peer reviewed, edited version of this article is published in Journal of Medical Microbiology, volume 68, issue10, 2019 http://dx.doi.org/10.1099/jmm.0.001060
Uncontrolled Keywords :	Synergy; Combination therapy; Wound infections; Gram-negative non-fermenters; Polyphenols
Depositing User :	Clive Harris
Date Deposited :	22 Aug 2019 08:49
Last Modified :	13 Dec 2019 12:58
URI:	http://epubs.surrey.ac.uk/id/eprint/852460

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