Abstract
Ever increasing numbers of antibiotic resistances are putting more and more pressure on research and global health systems. Multidrug-resistant bacteria even escape from second-line antibiotics and only a few promising candidates are presently in the pipeline. Intrinsic resistance of bacteria mediated by efflux pumps play a crucial role in the development and implementation of resistances. Efflux pump inhibitors represent one possible way to overcome this decreasing sensitivity of bacteria to antibiotics. The co-administration of such efflux pump inhibitors together with an antibiotic reduces the amount needed of the antibiotic for the same therapeutic effect by cutting side effects. These inhibitors have also the possibility to reactivate ineffective antibiotics again for therapy. Plants are facing constant bacterial exposure and are therefore a promising source for new efflux pump inhibitors due to the enormous compound diversity, low toxicity and high tolerability. Reviewing the literature, we herein present an update of newly discovered efflux pump inhibitors with plant-based origin against bacterial strains of concern. Various compounds from 23 different plants have been reported and evaluated for their potential as efflux pump inhibitors based on efflux and accumulation data. This review also discusses the hurdles of clinical implementation.
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Abbreviations
- AB:
-
Antibiotic
- CCCP:
-
Carbonyl cyanide m-chlorophenylhydrazone
- EP:
-
Efflux pump
- EPI:
-
Efflux pump inhibitor
- EtBr:
-
Ethidium bromide
- MDR:
-
Multidrug-resistant
- MIC:
-
Minimal inhibitory concentration
- MRSA:
-
Methicillin-resistant Staphylococcus aureus
- PAβN:
-
Phenylalanyl-arginyl-β-naphthylamide
- PMF:
-
Proton motive force
- QS:
-
Quorum sensing
References
Abreu A, McBain A, Simoes M (2012) Plants as sources of new antimicrobials and resistance-modifying agents. Nat Prod Rep 29:1007–1021
Adamson D, Krikstopaityte V, Coote P (2015) 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 70:2271–2278
Amaral L, Martins A, Spengler G, Molnar J (2014) Efflux pumps of gram-negative bacteria: what they do, how they do it, with what and how to deal with them. Front Pharmacol 4:168
Andries K, Villellas C, Coeck N, Thys K, Gevers T, Vranckx L, Lounis N, de Jong B, Koul A (2014) Acquired resistance of Mycobacterium tuberculosis to bedaquiline. PLoS One 9:e102135
Aparna V, Dineshkumar K, Mohanalakshmi N, Velmurugan D, Hopper W (2014) Identification of natural compound inhibitors for multidrug efflux pumps of Escherichia coli and Pseudomonas aeruginosa using in silico high-throughput virtual screening and in vitro validation. PLoS One 9:e101840
Assar N, Ibrahim Y, Abouwarda Am, Amin M (2012) The effect of clove extract on the minimum inhibitory concentration of ciprofloxacin in fluoroquinolone resistant clinical isolates of Staphylococcus aureus. Afr J Microbiol Res 6:1306–1311
Ball P, Shales S, Chopra I (1980) Plasmid-mediated tetracycline resistance in Escherichia coli involves increased efflux of the antibiotic. Biochem Biophys Res Commun 93:74–81
Bame J, Graf T, Junio H, Bussey R, Jarmusch S, El-Elimat T, Falkinham J, Oberlies N, Cech R, Cech N (2013) Sarothrin from Alkanna orientalis is an antimicrobial agent and efflux pump inhibitor. Planta Med 79:327–329
Berti L, Lorenzi V, Casanova J, Muselli A, Pages J, Bolla J (2010) Geraniol as bacterial efflux pump inhibitor. European Patent EP 2184061, 12 May 2010
Bharate J, Singh S, Wani A, Sharma S, Joshi P, Khan I, Kumar A, Vishwakarma R, Bharate S (2015) Discovery of 4-acetyl-3-(4-fluorophenyl)-1-(p-tolyl)-5-methylpyrrole as a dual inhibitor of human P-glycoprotein and Staphylococcus aureus Nor A efflux pump. Org Biomol Chem 13:5424–5431
Cabral V, Luo X, Junqueira E, Costa S, Mulhovo S, Duarte A, Couto I, Viveiros M, Ferreira M (2015) Enhancing activity of antibiotics against Staphylococcus aureus: Zanthoxylum capense constituents and derivatives. Phytomedicine 22:469–476
Chakrabarty S, Roy M, Hazra B, Bhattacharya R (2002) Induction of apoptosis in human cancer cell lines by diospyrin, a plant-derived bisnaphthoquinonoid, and its synthetic derivatives. Cancer Lett 188:85–93
Chan B, Han X, Lui S, Wong C, Wang T, Cheung D, Cheng S, Ip M, Han S, Yang X, Jolivalt C, Lau C, Leung P, Fung K (2015) Combating against methicillin-resistant Staphylococcus aureus—two fatty acids from purslane (Portulaca oleracea L.) exhibit synergistic effects with erythromycin. J Pharm Pharmacol 67:107–116
Chitemerere T, Mukanganyama S (2014) Evaluation of cell membrane integrity as a potential antimicrobial target for plant products. BMC Complement Altern Med 14:278
Chovanova R, Mezovska J, Vaverkova S, Mikulasova M (2015) The inhibition the Tet(K) efflux pump of tetracycline resistant Staphylococcus epidermidis by essential oils from three Salvia species. Lett Appl Microbiol 61:58–62
de Knegt G, Bakker-Woudenberg I, van Soolingen D, Aarnoutse R, Boeree M, de Steenwinkel J (2015) SILA-421 activity in vitro against rifampicin-susceptible and rifampicin-resistant Mycobacterium tuberculosis, and in vivo in a murine tuberculosis model. Int J Antimicrob Agents 46:66–72
Dwivedi G, Maurya A, Yadav D, Khan F, Darokar M, Srivastava S (2014) Drug resistance reversal potential of ursolic acid derivatives against nalidixic acid- and multidrug-resistant Escherichia coli. Chem Biol Drug Des. doi:10.1111/cbdd.12491
Fernández L, Hancock R (2012) Adaptive and mutational resistance: role of porins and efflux pumps in drug resistance. Clin Microbiol Rev 25:661–681
Ferreira S, Silva F, Queiroz J, Oleastro M, Domingues F (2014) Resveratrol against Arcobacter butzleri and Arcobacter cryaerophilus: activity and effect on cellular functions. Int J Food Microbiol 180:62–68
Freire-Moran L, Aronsson B, Manz C, Gyssens I, So A, Monnet D, Cars O (2011) Critical shortage of new antibiotics in development against multidrug-resistant bacteria-time to react is now. Drug Resist Update 14:118–124
Friedenberg W, Rue M, Blood E, Dalton W, Shustik C, Larson R, Sonneveld P, Greipp P (2006) Phase III study of PSC-833 (valspodar) in combination with vincristine, doxorubicin, and dexamethasone (valspodar/VAD) versus VAD alone in patients with recurring or refractory multiple myeloma (E1A95): a trial of the Eastern cooperative oncology group. Cancer 106:830–838
Garvey M, Piddock L (2008) The efflux pump inhibitor reserpine selects multidrug-resistant Streptococcus pneumoniae strains that overexpress the ABC transporters PatA and PatB. Antimicrob Agents Chemother 52:1677–1685
Garvey M, Rahman M, Gibbons S, Piddock L (2011) Medicinal plant extracts with efflux inhibitory activity against Gram-negative bacteria. Int J Antimicrob Agents 37:145–151
Gavrish E, Sit C, Cao S, Kandror O, Spoering A, Peoples A, Ling L, Fetterman A, Hughes D, Bissell A, Torrey H, Akopian T, Mueller A, Epstein S, Goldberg A, Clardy J, Lewis K (2014) Lassomycin, a ribosomally synthesized cyclic peptide, kills Mycobacterium tuberculosis by targeting the ATP-dependent protease ClpC1P1P2. Chem Biol 21:509–518
Groeblacher B, Kunert O, Bucar F (2012a) Compounds of Alpinia katsumadai as potential efflux inhibitors in Mycobacterium smegmatis. Bioorg Med Chem 20:2701–2706
Groeblacher B, Maier V, Kunert O, Bucar F (2012b) Putative mycobacterial efflux inhibitors from the seeds of Aframomum melegueta. J Nat Prod 75:1393–1399
Grossman T, Shoen C, Jones S, Jones P, Cynamon M, Locher C (2015) The efflux pump inhibitor timcodar improves the potency of antimycobacterial agents. Antimicrob Agents Chemother 59:1534–1541
Gupta S, Tyagi S, Bishai W (2015) Verapamil increases the bactericidal activity of bedaquiline against Mycobacterium tuberculosis in a mouse model. Antimicrob Agents Chemother 59:673–676
Herrmann F, Wink M (2011) Synergistic interactions of saponins and monoterpenes in HeLa cells, Cos7 cells and in erythrocytes. Phytomedicine 18:1191–1196
Junwei W, Jing Z, Sanxia L, Xiaohong S, Yongle L, Baorui M, Yangmei Z, Xiaoli L, Chengzhu Y, Qingqing L (2013a) Application of liquiritin in preparing Escherichia coli fluoroquinolone efflux pump inhibitor. Chinese Patent CN 102988400, 27 March 2013
Junwei W, Jing Z, Sanxia L, Xiaohong S, Yongle L, Baorui M, Yangmei Z, Xiaoli L, Chengzhu Y, Qingqing L (2013b) Application of tetrandrine in preparing Escherichia coli fluoroquinolone efflux pump inhibitor. Chinese Patent CN 103202841, 17 July 2013
Kalia N, Mahajan P, Mehra R, Nargotra A, Sharma J, Koul S, Khan I (2012) Capsaicin, a novel inhibitor of the NorA efflux pump, reduces the intracellular invasion of Staphylococcus aureus. J Antimicrob Chemother 67:2401–2408
Kenichi F (2012) Drug efflux inhibitors containing phenylpropanoids, antibacterial activity promoter and anticancer activity promoter. Japanese Patent JP 2012224561, 15 Nov 2012
Kourtesi C, Ball A, Huang Y, Jachak S, Vera D, Khondkar P, Gibbons S, Hamblin M, Tegos G (2013) Microbial efflux systems and inhibitors: approaches to drug discovery and the challenge of clinical implementation. Open Microbiol J 7:34–52
Kovac J, Gavaric N, Bucar F, Mozina S (2014) Antimicrobial and resistance modulatory activity of Alpinia katsumadai seed phenolic extract, essential oil and post-distillation extract. Food Technol Biotechnol 52:248–254
Kovac J, Simunovic K, Wu Z, Klancnik A, Bucar F, Zhang Q, Mozina S (2015) Antibiotic resistance modulation and modes of action of (−)-alpha-pinene in Campylobacter jejuni. PLoS One 10:e0122871
Lechner D, Gibbon S, Bucar F (2008) Plant phenolic compounds as ethidium bromide efflux inhibitors in Mycobacterium smegmatis. J Antimicrob Chemother 62:345–348
Lewis J, Owens A, Cadena J, Sabol K, Patterson J, Jorgensen J (2005) Emergence of daptomycin resistance in Enterococcus faecium during daptomycin therapy. Antimicrob Agents Chemother 49:1664–1665
Limtrakul P, Khantamat O, Pintha K (2005) Inhibition of P-glycoprotein function and expression by kaempferol and quercetin. J Chemother 17:86–95
Ling L, Schneider T, Peoples A, Spoering A, Engels I, Conlon B, Mueller A, Schaberle T, Hughes D, Epstein S, Jones M, Lazarides L, Steadman V, Cohen D, Felix C, Fetterman K, Millett W, Nitti A, Zullo A, Chen C, Lewis K (2015) A new antibiotic kills pathogens without detectable resistance. Nature 517:455–459
Lomovskaya O, Bostian K (2006) Practical applications and feasibility of efflux pump inhibitors in the clinic—a vision for applied use. Biochem Pharmacol 71:910–918
Lomovskaya O, Warren M, Lee A, Galazzo J, Fronko R, Lee M, Blais J, Cho D, Chamberland S, Renau T, Leger R, Hecker S, Watkins W, Hoshino K, Ishida H, Lee V (2001) Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: novel agents for combination therapy. Antimicrob Agents Chemother 45:105–116
Maisuria V, Hosseinidoust Z, Tufenkji N (2015) Polyphenolic extract from maple syrup potentiates antibiotic susceptibility and reduces biofilm formation of pathogenic bacteria. Appl Environ Microbiol 81:3782–3792
Matsui H, Schwartz A (1968) Mechanism of cardiac glycoside inhibition of the (Na+-K+)-dependent ATPase from cardiac tissue. Biochim Biophys Acta 151:655–663
Maurya A, Dwivedi G, Darokar M, Srivastava S (2013) Antibacterial and synergy of clavine alkaloid lysergol and its derivatives against nalidixic acid-resistant Escherichia coli. Chem Biol Drug Des 81:484–490
McMurry L, Petrucci R Jr, Levy S (1980) Active efflux of tetracycline encoded by four genetically different tetracycline resistance determinants in Escherichia coli. Proc Natl Acad Sci USA 77:3974–3977
Mirza Z, Kumar A, Kalia N, Zargar A, Khan I (2011) Piperine as an inhibitor of the MdeA efflux pump of Staphylococcus aureus. J Med Microbiol 60:1472–1478
Mukanganyama S, Chirisa E, Hazra B (2012) Antimycobacterial activity of diospyrin and its derivatives against Mycobacterium aurum. Res Pharm 2:1–13
Newman D, Cragg G (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod 75:311–335
Ojeda-Sana A, Repetto V, Moreno S (2013) Carnosic acid is an efflux pumps modulator by dissipation of the membrane potential in Enterococcus faecalis and Staphylococcus aureus. World J Microbiol Biotechnol 29:137–144
Oluwatuyi M, Kaatz G, Gibbons S (2004) Antibacterial and resistance modifying activity of Rosmarinus officinalis. Phytochemistry 65:3249–3254
Putman M, van Veen H, Konings W (2000) Molecular properties of bacterial multidrug transporters. Microbiol Mol Biol Rev 64:672–693
Ramalhete C, Molnár J, Mulhovo S, Rosário V, Ferreira M (2009) New potent P-glycoprotein modulators with the cucurbitane scaffold and their synergistic interaction with doxorubicin on resistant cancer cells. Bioorg Med Chem 17:6942–6951
Ramalhete C, Spengler G, Martins A, Martins M, Viveiros M, Mulhovo S, Ferreira M, Amaral L (2011) Inhibition of efflux pumps in meticillin-resistant Staphylococcus aureus and Enterococcus faecalis resistant strains by triterpenoids from Momordica balsamina. Int J Antimicrob Agents 37:70–74
Rice L (2008) Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE. J Infect Dis 197:1079–1081
Roche (2015) Roche, Meiji and Fedora join forces to tackle increasing bacterial resistance to antibiotics. http://www.roche.com/media/store/releases/med-cor-2015-01-13.htm
Roy S, Pahwa S, Nandanwar H, Jachak S (2012) Phenylpropanoids of Alpinia galanga as efflux pump inhibitors in Mycobacterium smegmatis mc2 155. Fitoterapia 83:1248–1255
Roy S, Kumari N, Gupta S, Pahwa S, Nandanwar H, Jachak S (2013a) 7-Hydroxy-(E)-3-phenylmethylene-chroman-4-one analogues as efflux pump inhibitors against Mycobacterium smegmatis mc(2) 155. Eur J Med Chem 66:499–507
Roy S, Kumari N, Pahwa S, Agrahari U, Bhutani K, Jachak S, Newman D (2013b) NorA efflux pump inhibitory activity of coumarins from Mesua ferrea. Fitoterapia 90:140–150
Savoia D (2012) Plant-derived antimicrobial compounds: alternatives to antibiotics. Future Microbiol 7:979–990
Sewanu S, Bongekile M, Folusho O, Adejumobi L, Rowland O (2015) Antimicrobial and efflux pumps inhibitory activities of Eucalyptus grandis essential oil against respiratory tract infectious bacteria. J Med Plant Res 9:343–348
Shiu W, Malkinson J, Rahman M, Curry J, Stapleton P, Gunaratnam M, Neidle S, Mushtaq S, Warner M, Livermore D, Evangelopoulos D, Basavannacharya C, Bhakta S, Schindler B, Seo S, Coleman D, Kaatz G, Gibbons S (2013) A new plant-derived antibacterial is an inhibitor of efflux pumps in Staphylococcus aureus. Int J Antimicrob Agents 42:513–518
Stavri M, Piddock L, Gibbons S (2007) Bacterial efflux pump inhibitors from natural sources. J Antimicrob Chemother 59:1247–1260
Sun J, Deng Z, Yan A (2014) Bacterial multidrug efflux pumps: mechanisms, physiology and pharmacological exploitations. Biochem Biophys Res Commun 453:254–267
The Plant List (2013) Version 1.1. http://www.theplantlist.org/
Tsiodras S, Gold H, Sakoulas G, Eliopoulos G, Wennersten C, Venkataraman L, Moellering R, Ferraro M (2001) Linezolid resistance in a clinical isolate of Staphylococcus aureus. Lancet 358:207–208
U.S. Food and Drug Administration (2015). http://www.fda.gov/default.htm. Accessed 22 May 2015
Varga Z, Armada A, Cerca P, Amaral L, Mior Ahmad Subki M, Savka M, Szegedi E, Kawase M, Motohashi N, Molnar J (2012) Inhibition of quorum sensing and efflux pump system by trifluoromethyl ketone proton pump inhibitors. In Vivo 26:277–285
Velayati A, Masjedi M, Farnia P, Tabarsi P, Ghanavi J, Ziazarifi A, Hoffner S (2009) Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug-resistant strains in Iran. Chest 136:420–425
WHO (2014) Antimicrobial resistance global report on surveillance. Global report on surveillance. http://www.who.int/drugresistance/documents/surveillancereport/en/
Yoshida K, Nakayama K, Ohtsuka M, Kuru N, Yokomizo Y, Sakamoto A, Takemura M, Hoshino K, Kanda H, Nitanai H, Namba K, Yoshida K, Imamura Y, Zhang J, Lee V, Watkins W (2007) MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 7: highly soluble and in vivo active quaternary ammonium analogue D13-9001, a potential preclinical candidate. Bioorg Med Chem 15:7087–7097
Zhang J, Sun Y, Wang Y, Lu M, He J, Liu J, Chen Q, Zhang X, Zhou F, Wang G, Sun X (2014) Non-antibiotic agent ginsenoside 20(S)-Rh2 enhanced the antibacterial effects of ciprofloxacin in vitro and in vivo as a potential NorA inhibitor. Eur J Pharmacol 740:277–284
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Authors thank the University of Graz for funding this Ph.D. project with the stipend ‘Forschungsstipendium für Doktorandinnen’.
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Prasch, S., Bucar, F. Plant derived inhibitors of bacterial efflux pumps: an update. Phytochem Rev 14, 961–974 (2015). https://doi.org/10.1007/s11101-015-9436-y
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DOI: https://doi.org/10.1007/s11101-015-9436-y