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BMC Complementary Medicine and Therapies
Published in: BMC Complementary Medicine and Therapies 1/2018

Open Access 01-12-2018 | Research article

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

Authors: Thanyaluck Siriyong, Supayang Piyawan Voravuthikunchai, Peter John Coote

Published in: BMC Complementary Medicine and Therapies | Issue 1/2018

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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.
Appendix
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Literature
1.
Lister PD, Wolter DJ, Hanson ND. Antibacterial-resistant Pseudomonas aeruginosa: clinical impact and complex regulation of chromosomally encoded resistance mechanisms. Clin Microbiol Rev. 2009;22:582–610.CrossRef
2.
Piddock LJ. Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin Microbiol Rev. 2006;19:382–402.CrossRef
3.
Poole K. Pseudomonas Aeruginosa: Resistance to the Max. Front Microbiol. 2011;2:65.CrossRef
4.
Tegos GP, Haynes M, Strouse JJ, Khan MM, Bologa CG, Oprea TI, et al. Microbial efflux pump inhibition: tactics and strategies. Curr Pharm Des. 2011;17:1291–302.CrossRef
5.
Bohnert JA, Kern WV. Antimicrobial drug efflux pump inhibitors. In: Li XZ, et al., editors. Efflux-Mediated Antimicrobial Resistance in Bacteria. Switzerland: Springer International Publishing; 2016. p. 755–95.CrossRef
6.
Sun J, Deng Z, Yan A. Bacterial multidrug efflux pumps: mechanisms, physiology and pharmacological exploitations. Biochem Biophys Res Commun. 2014;453:254–67.CrossRef
7.
Bohnert JA, Szymaniak-Vits M, Schuster S, Kern WV. Efflux inhibition by selective serotonin reuptake inhibitors in Escherichia coli. J Antimicrob Chemother. 2011;66:2057–60.CrossRef
8.
Piddock LJV, Garvey MI, Rahman MM, Gibbons S. Natural and synthetic compounds such as trimethoprim behave as inhibitors of efflux in gram-negative bacteria. J Antimicrob Chemother. 2010;65:1215–23.CrossRef
9.
Morita Y, Nakashima K, Nishino K, Kotani K, Tomida J, Inoue M, et al. Berberine is a novel type efflux inhibitor which attenuates the MexXY-mediated aminoglycoside resistance in Pseudomonas aeruginosa. Front Microbiol. 2016;7:1223.CrossRef
10.
E B, PJ C. Enhancement of antibiotic efficacy against multi-drug resistant Pseudomonas aeruginosa infections via combination with curcumin and 1-(1-Naphthylmethyl)-piperazine. J Antimicrob Agents. 2016;2:116.
11.
Negi N, Prakash P, Gupta ML, Mohapatra TM. Possible role of curcumin as an efflux pump inhibitor in multidrug resistant clinical isolates of Pseudomonas aeruginosa. J Clin Diagn Res. 2014;8:DC04–7.PubMedPubMedCentral
12.
Choudhury D, Talukdar AD, Chetia P, Bhattacharjee A, Choudhury MD. Screening of natural products and derivatives for the identification of RND efflux pump inhibitors. Comb Chem High Throughput Screen. 2016;19:705–13.CrossRef
13.
Prasch S, Bucar F. Plant derived inhibitors of bacterial efflux pumps: an update. Phytochem Rev. 2015;14:961–74.CrossRef
14.
Stavri M, Piddock LJV, Gibbons S. Bacterial efflux pump inhibitors from natural sources. J Antimicrob Chemother. 2007;59:1247–60.CrossRef
15.
Chakraborty A, Brantner AH. Antibacterial steroid alkaloids from the stem bark of Holarrhena pubescens. J Ethnopharmacol. 1999;68:339–44.CrossRef
16.
Kumar N, Singh B, Bhandari P, Gupta AP, Kaul VK. Steroidal alkaloids from Holarrhena antidysenterica (L.) WALL. Chem Pharm Bull. 2007;55:912–4.CrossRef
17.
Chusri S, Siriyong T, Na-Phatthalung P, Voravuthikunchai SP. Synergistic effects of ethnomedicinal plants of Apocynaceae family and antibiotics against clinical isolates of Acinetobacter baumannii. Asian Pac J Trop Med. 2014;7:456–61.CrossRef
18.
Phatthalung PN, Chusri S, Voravuthikunchai SP. Thai ethnomedicinal plants as resistant modifying agents for combating Acinetobacter baumannii infections. BMC Complement Altern Med. 2012;12:56.CrossRef
19.
Siriyong T, Chusri S, Srimanote P, Tipmanee V, Voravuthikunchai SP. Holarrhena antidysenterica extract and its steroidal alkaloid, conessine, as resistance-modifying agents against extensively drug-resistant Acinetobacter baumannii. Microb Drug Resist. 2016;22:273–82.CrossRef
20.
Siriyong T, Srimanote P, Chusri S, Yingyongnarongkul B, Suaisom C, Tipmanee V, et al. Conessine as a novel inhibitor of multidrug efflux pump systems in Pseudomonas aeruginosa. BMC Complement Altern Med. 2017;17:405.CrossRef
21.
Adamson DH, Krikstopaityte V, Coote PJ. Enhanced efficacy of putative efflux pump inhibitor/antibiotic combination treatments versus MDR strains of Pseudomonas aeruginosa in a Galleria mellonella in vivo infection model. J Antimicrob Chemother. 2015;70:2271–8.CrossRef
22.
Lomovskaya O, Lee A, Hoshino K, Ishida H, Mistry A, Warren MS, et al. Use of a genetic approach to evaluate the consequences of inhibition of efflux pumps in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1999;43:1340–6.CrossRef
23.
Hill L, Veli N, Coote PJ. Evaluation of Galleria mellonella larvae for measuring the efficacy and pharmacokinetics of antibiotic therapies against Pseudomonas aeruginosa infection. Int J Antimicrob Agents. 2014;43:254–61.CrossRef
24.
Eliopoulous G, Moellering R. Antimicrobial combinations. In: Lorian V, editor. Antibiotics in Laboratory Medicine 3. Baltimore: Williams and Wilkins; 1996. p. 330–96.
25.
White RL, Burgess DS, Manduru M, Bosso JA. Comparison of three different in vitro methods of detecting synergy: time-kill, checkerboard, and E test. Antimicrob Agents Chemother. 1996;40:1914–8.CrossRef
26.
Krezdorn J, Adams S, Coote PJ. A Galleria mellonella infection model reveals double and triple antibiotic combination therapies with enhanced efficacy versus a multidrug-resistant strain of Pseudomonas aeruginosa. J Med Microbiol. 2014;63:945–55.CrossRef
27.
Bland JM, Altman DG. Survival probabilities (the Kaplan-Meier method). Brit Med J. 1998;317:1572.CrossRef
28.
29.
Holm S. A simple sequentially rejective multiple test procedure. Scand J Stat. 1979;6:65–70.
30.
Damier-Piolle L, Magnet S, Bremont S, Lambert T, Courvalin P. AdeIJK, a resistance-nodulation-cell division pump effluxing multiple antibiotics in Acinetobacter baumannii. Antimicrob Agents Chemother. 2008;52:557–62.CrossRef
31.
Bogne KP, Penlap BV, Mbofung CM, Etoa F-X. Acute and subacute toxicity of the methanol extract from Holarrhena floribunda G. Don (Apocynaceae). Europ. J Exp Biol. 2012;2:1284–8.
32.
Stephenson RP. The pharmacological properties of conessine, isoconessine and neoconessine. Brit J Pharmacol. 1948;3:237–45.PubMed
Metadata
Title
Steroidal alkaloids and conessine from the medicinal plant Holarrhena antidysenterica restore antibiotic efficacy in a Galleria mellonella model of multidrug-resistant Pseudomonas aeruginosa infection
Authors
Thanyaluck Siriyong
Supayang Piyawan Voravuthikunchai
Peter John Coote
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2018
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-018-2348-9

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