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Potent anti-MRSA activity and synergism with aminoglycosides by flavonoid derivatives from the root barks of Morus alba, a traditional Chinese medicine

  • Guo-Ying ZuoEmail author
  • Cui-Xian Yang
  • Zhao-Juan Ruan
  • Jun HanEmail author
  • Gen-Chun Wang
Original Research
  • 6 Downloads

Abstract

Infections of clinical methicillin-resistant Staphylococcus aureus (MRSA) is a very tough public health problem and a challenge of new drug development. Nearly 90 Diels-Alder adducts (DAAs) have so far been isolated from Morus plants, but only a few of them have been evaluated for their anti-MRSA activities. To study the antibacterial compounds of DAAs from the root barks’ section of Morus alba L. and their synergism with antibacterial agents against clinical MRSA strains, bioassay-guided phytochemical methods were used to screen the active components. Minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) were assayed through broth serial microdilution. The synergism were evaluated by checker board microdilution and dynamic time-kill experiments. Three DAAs (multicaulisin (1), sanggenon G (2) and albanin G (3)) were isolated and identified from M. alba root barks. They were determined with potent effect against MRSA isolates with MICs/MBCs at 2–8/16–128 mg/L. They also showed synergy with conventional antibacterial agents, especially the aminoglycosides, with fractional inhibitory concentration indices (FICIs) ranged from 0.19 to 0.50 and the dose reduction indices (DRIs) ranged from 16 to 2. The MRSA resistance to the antibiotics could be reversed by compounds 13. The dose-dependent bactericidal synergism against MRSA was observed as well. The study released for the first time the anti-MRSA synergism of DAAs from M. alba root barks with antibacterial agents and the reversal of MRSA resistance to aminoglycosides. The results may be valuable for further development of new antibacterial drugs and synergists against MRSA infections.

Keywords

MRSA Morus alba Diels-Alder adduct Aminoglycoside Synergy Resistance reversal effect 

List of abbreviations

AG

albanin G

Ak

amikacin

AMR

antimicrobial resistance

CFU

colony forming unit

CBMD

checker board microdilution

CLSI

Clinical and Laboratory Standards Institute

DAA

Diels-Alder adduct

DRI

dose reduction index

Em

etimicin

Gm

gentamicin

FICI

fractional inhibitory concentration index

I

intermediate

Le

levofloxacin

MBC

minimal bactericidal concentration

M-H

Mueller-Hinton medium

MIC

minimal inhibitory concentration

MSSA

methicillin-susceptible Staphylococcus aureus

MRSA

methicillin-resistant Staphylococcus aureus

Mu

multicaulisin

NMR

nuclear magnetic resonance

R

resistant

S

susceptible

SBP

Sang-Bai-Pi (root barks of Morus alba L. (Moraceae))

SG

sanggenon G

T-KC

time-killing curve

Va

vancomycin

Notes

Acknowledgements

The research was supported from No 81173504 (NSFC, China) and 2008PY001 (Yunnan Province, China). The authors wish to thank Kunming Institute of Botany (KIB, CAS) for spectral analysis.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2019_2393_MOESM1_ESM.pdf (337 kb)
Supplementary material

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Research Center for Natural MedicinesKunming General Hospital of Chengdu Military CommandKunmingChina
  2. 2.Yunnan Traditional Chinese Medical CollegeKunmingChina

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