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Steroidal alkaloids and conessine from the medicinal plant Holarrhena antidysenterica restore antibiotic efficacy in a Galleria mellonella model of multidrug-resistant Pseudomonas aeruginosa infection

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Date
19/10/2018
Author
Siriyong, Thanyaluck
Voravuthikunchai, Supayang Piyawan
Coote, Peter John
Keywords
Conessine
Efflux pump inhibitor
Galleria mellonella
Holarrhena antidysenterica
Mex efflux systems
RV Botanic, Thomsonian, and eclectic medicine
DAS
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Abstract
Background This study aimed to evaluate the efficacy of combinations of steroidal alkaloids and conessine from the Thai medicinal plant Holarrhena antidysenterica with antibiotics against Pseudomonas aeruginosa strains possessing different efflux-pump-mediated multidrug-resistant (MDR) phenotypes in a Galleria mellonella infection model. Methods P. aeruginosa strains with defined mutations that result in the overexpression of the MexAB-OprM, MexCD-OprJ and MexEF-OprN efflux pumps, and a strain with all three of these pumps deleted, were used. In vitro, the effect of combinations of steroidal alkaloids and conessine with antibiotics was compared with antibiotic treatment alone via MIC determination and time-kill assays. Efficacy of combinations of the steroidal alkaloids and conessine with levofloxacin were compared with monotherapies against infections in G. mellonella larvae by measuring larval mortality and bacterial burden. Results Combination therapies of conessine or steroidal alkaloids with levofloxacin enhanced bacterial inhibition in vitro and restored antibiotic efficacy in vivo compared to the constituent monotherapies. Neither conessine nor the steroidal alkaloids induced any detectable toxicity in G. mellonella larvae. The enhanced efficacy of the combination treatments was most pronounced with conessine and correlated with reduced larval burden of infecting P. aeruginosa. Notably, the enhanced efficacy of conessine/levofloxacin combinations was only detected in the parent strain and strains that overexpressed the MexAB-OprM or MexEF-OprN efflux systems. Conclusions Steroidal alkaloids from Holarrhena antidysenterica, and particularly the principal active ingredient conessine, restored levofloxacin efficacy against resistant P. aeruginosa strains possessing efflux-mediated MDR phenotypes. The compounds should be investigated further as a potential novel therapy.
Citation
Siriyong , T , Voravuthikunchai , S P & Coote , P J 2018 , ' Steroidal alkaloids and conessine from the medicinal plant Holarrhena antidysenterica restore antibiotic efficacy in a Galleria mellonella model of multidrug-resistant Pseudomonas aeruginosa infection ' , BMC Complementary and Alternative Medicine , vol. 18 , 285 . https://doi.org/10.1186/s12906-018-2348-9
Publication
BMC Complementary and Alternative Medicine
Status
Peer reviewed
DOI
https://doi.org/10.1186/s12906-018-2348-9
ISSN
1472-6882
Type
Journal article
Rights
© The Author(s). 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Description
This work was supported by the Thailand Research Fund through the Royal Golden Jubilee Ph.D. Program (Grant No. PHD/0041/2556) co-funded by the Newton Fund of the British Council and TRF Senior Research Scholar (Grant No. RTA 5880005).
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  • University of St Andrews Research
URI
http://hdl.handle.net/10023/16312

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