Reversal of Tetracycline Resistance by Cepharanthine, Cinchonidine, Ellagic Acid and Propyl Gallate in a Multi-drug Resi
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ORIGINAL ARTICLE
Reversal of Tetracycline Resistance by Cepharanthine, Cinchonidine, Ellagic Acid and Propyl Gallate in a Multi‑drug Resistant Escherichia coli Darko Jenic1 · Helen Waller2 · Helen Collins3 · Clett Erridge1 Received: 20 August 2020 / Accepted: 27 October 2020 © The Author(s) 2020
Abstract Bacterial resistance to antibiotics is an increasing threat to global healthcare systems. We therefore sought compounds with potential to reverse antibiotic resistance in a clinically relevant multi-drug resistant isolate of Escherichia coli (NCTC 13400). 200 natural compounds with a history of either safe oral use in man, or as a component of a traditional herb or medicine, were screened. Four compounds; ellagic acid, propyl gallate, cinchonidine and cepharanthine, lowered the minimum inhibitory concentrations (MICs) of tetracycline, chloramphenicol and tobramycin by up to fourfold, and when combined up to eightfold. These compounds had no impact on the MICs of ampicillin, erythromycin or trimethoprim. Mechanistic studies revealed that while cepharanthine potently suppressed efflux of the marker Nile red from bacterial cells, the other hit compounds slowed cellular accumulation of this marker, and/or slowed bacterial growth in the absence of antibiotic. Although cepharanthine showed some toxicity in a cultured HEK-293 mammalian cell-line model, the other hit compounds exhibited no toxicity at concentrations where they are active against E. coli NCTC 13400. The results suggest that phytochemicals with capacity to reverse antibiotic resistance may be more common in traditional medicines than previously appreciated, and may offer useful scaffolds for the development of antibiotic-sensitising drugs.
* Clett Erridge [email protected] 1
School of Life Sciences, Anglia Ruskin University, East Road, Cambridge CB1 1PT, UK
2
Diabetes Research Centre, University of Leicester, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, UK
3
Department of Health Sciences, University of Leicester, University Rd, Leicester LE1 7RH, UK
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Graphic Abstract
Keywords Antibiotic resistance · Natural products · Phytochemical · Screening · Efflux pump inhibitor
1 Introduction Gram-negative bacteria displaying resistance to multiple classes of antibiotics are increasingly prevalent and difficult to treat in modern healthcare systems [1]. Historically, this issue has been countered by the discovery and development of new classes of antibiotics. However, as only two new classes of antibiotic have been discovered since the 1960s, attention has focussed more recently on the identification of agents which target bacterial mechanisms of resistance [2, 3]. This approach has proven successful for the restoration of utility of some β-lactam antibiotics via lactamase inhibitors, such as clavulanic acid [3]. Some success has also been reported in the identification of compounds with capacity to reverse resistance to various non-lactam antibiotics in Gram-positive bacteria, par
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