整合生物学期刊网

应用天然产物 ›› 2021, Vol. 11 ›› Issue (3): 345-356.DOI: 10.1007/s13659-020-00280-y

• ORIGINAL ARTICLES • 上一篇    下一篇

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   

  1. 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
  • 收稿日期:2020-08-20 修回日期:2020-10-27 出版日期:2021-06-24 发布日期:2021-06-04
  • 通讯作者: Clett Erridge
  • 基金资助:
    This work was supported by an Erasmus+ Mobility Studentship (ref DK KOBENHA 57) awarded to DJ. The funder was not involved in the interpretation of results or writing of the 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   

  1. 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
  • Received:2020-08-20 Revised:2020-10-27 Online:2021-06-24 Published:2021-06-04
  • Contact: Clett Erridge
  • Supported by:
    This work was supported by an Erasmus+ Mobility Studentship (ref DK KOBENHA 57) awarded to DJ. The funder was not involved in the interpretation of results or writing of the article.

摘要: 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.

关键词: Antibiotic resistance, Natural products, Phytochemical, Screening, Efflux pump inhibitor

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.

Key words: Antibiotic resistance, Natural products, Phytochemical, Screening, Efflux pump inhibitor