Molecular Biology Reports

, Volume 46, Issue 2, pp 2395–2404 | Cite as

Antibacterial effects of curcumin encapsulated in nanoparticles on clinical isolates of Pseudomonas aeruginosa through downregulation of efflux pumps

  • Saeid Rahbar Takrami
  • Najmeh RanjiEmail author
  • Majid Sadeghizadeh
Original Article


Curcumin as a flavonoid from the rhizome of Curcuma longa has antibacterial, antiviral and antifungal activity. Multidrug resistance in pathogenic bacteria is continuously increasing in hospitals. The aim of this study was to investigate the effect of curcumin encapsulated in micellar/polymersome nanoparticles as an efflux pump inhibitor (EPI) on the expression of mexX and oprM genes in curcumin-treated and -untreated isolates of Pseudomonas aeruginosa. Clinical isolates of Pseudomonas aeruginosa were treated with ciprofloxacin (sub-MICs) alone and/or in combination with curcumin-encapsulated in micellar/polymersome nanoparticles. The expression of mexX and oprM genes was quantitatively evaluated by qRT-PCR in curcumin-treated and -untreated bacteria after 24 h. Curcumin-encapsulated in nanoparticles (400 µg/mL) induced cell death up to 50% in ciprofloxacin-treated (1/2MIC) resistant isolates during 24 h, while the bacteria treated with ciprofloxacin (without curcumin) were not inhibited. Also, curcumin in different concentrations increased effect of ciprofloxacin (sub-MICs). Downregulation of mexX and oprM genes was observed in cells treated with curcumin and ciprofloxacin compared to cells treated with ciprofloxacin alone. It seems that curcumin can be used as complementary drug in ciprofloxacin-resistant isolates through downregulating genes involved in efflux pumps and trapping ciprofloxacin on bacterial cells and increasing the effects of drug.


Ciprofloxacin Curcumin MexX Micellar/polymersome nanoparticles Pseudomonas aeruginosa OprM 



Hereby, we appreciate Dr. Farhood Najafi for synthesis of CMN. We also would like to thank Seyed Reza Garakoui for his cooperation.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest.


  1. 1.
    Venter H, Mowla R, Ohene-Agyei T, Ma S (2015) RND-type drug e ffl ux pumps from Gram-negative bacteria: molecular mechanism and inhibition. Front Microbiol 6:377CrossRefGoogle Scholar
  2. 2.
    Negi N, Prakash P, Gupta ML, Mohapatra TM (2014) Possible role of curcumin as an efflux pump inhibitor in multi drug resistant clinical isolates of Pseudomonas aeruginosa. J Clin Diagn Res 8::DC04–D7Google Scholar
  3. 3.
    Nouri R, Rezaee MA, Hasani A, Aghazadeh M, Asgharzadeh M (2016) The role of gyrA and parC mutations in fluoroquinolones-resistant Pseudomonas aeruginosa isolates from Iran. Braz J Microbiol 47:925–930CrossRefGoogle Scholar
  4. 4.
    Blanco P, Hernando-Amado S, Reales-Calderon JA, Corona F, Lira F, Alcalde-Rico M, Bernardini A, Sanchez MB, Martinez JL (2016) Bacterial Multidrug Efflux Pumps: Much More Than Antibiotic Resistance Determinants. Microorganisms 4Google Scholar
  5. 5.
    Ballard E, Coote PJ (2016) Enhancement of antibiotic efficacy against multi-drug resistant Pseudomonas aeruginosa infections via combination with curcumin and 1-(1-naphthylmethyl)-piperazine. J Antimicrob Agents 2Google Scholar
  6. 6.
    Poole K (2011) Pseudomonas aeruginosa: resistance to the max. Front Microbiol 2:65CrossRefGoogle Scholar
  7. 7.
    Esquisabel ABC, Rodriguez MC, Campo-Sosa AO, Rodriguez C, Martinez-Martinez L (2011) Mechanisms of resistance in clinical isolates of Pseudomonas aeruginosa less susceptible to cefepime than to ceftazidime. Clin Microbiol Infect 17:1817–1822CrossRefGoogle Scholar
  8. 8.
    Tyagi P, Singh M, Kumari H, Kumari A, Mukhopadhyay K (2015) Bactericidal activity of curcumin I is associated with damaging of bacterial membrane. PLoS ONE 10:e0121313CrossRefGoogle Scholar
  9. 9.
    Teow SY, Liew K, Ali SA, Khoo AS, Peh SC (2016) Antibacterial action of curcumin against Staphylococcus aureus: a brief review. J Trop Med 2016:2853045Google Scholar
  10. 10.
    Erfani-Moghadam V, Nomani A, Zamani M, Yazdani Y, Najafi F, Sadeghizadeh M (2014) A novel diblock of copolymer of (monomethoxy poly [ethylene glycol]-oleate) with a small hydrophobic fraction to make stable micelles/polymersomes for curcumin delivery to cancer cells. Int J Nanomed 9:5541–5554CrossRefGoogle Scholar
  11. 11.
    Meng B, Li J, Cao H (2013) Antioxidant and antiinflammatory activities of curcumin on diabetes mellitus and its complications. Curr Pharm Des 19:2101–2113Google Scholar
  12. 12.
    Moghadamtousi SZ, Kadir HA, Hassandarvish P, Tajik H, Abubakar S, Zandi K (2014) A review on antibacterial, antiviral, and antifungal activity of curcumin. Biomed Res Int 2014:186864Google Scholar
  13. 13.
    Sasidharan NK, Sreekala SR, Jacob J, Nambisan B (2014) In vitro synergistic effect of curcumin in combination with third generation cephalosporins against bacteria associated with infectious diarrhea. Biomed Res Int 2014:561456Google Scholar
  14. 14.
    Kourtesi C, Ball AR, Huang YY, Jachak SM, Vera DM, Khondkar P, Gibbons S, Hamblin MR, Tegos GP (2013) Microbial efflux systems and inhibitors: approaches to drug discovery and the challenge of clinical implementation. Open Microbiol J 7:34–52CrossRefGoogle Scholar
  15. 15.
    Cockerill F, Patel J, Alder J, Bradford P, Dudley M, Eliopoulos G (2013) Performance standards for antimicrobial susceptibility testing: twenty-third informational supplement; M100-S23. CLSI, WayneGoogle Scholar
  16. 16.
    Gorgani N, Ahlbrand S, Patterson A, Pourmand N (2009) Detection of point mutations associated with antibiotic resistance in Pseudomonas aeruginosa. Int J Antimicrob Agents 34:414–418CrossRefGoogle Scholar
  17. 17.
    Rahbar Takrami S, Ranji N, Hakimi F (2017) New mutations in ciprofloxacin resistant strains of pseudomonas aeruginosa isolated from Guilan Province, Northern Iran. Mol Genet Microbiol Virol 32:218–223CrossRefGoogle Scholar
  18. 18.
    Sobel ML, Hocquet D, Cao L, Plesiat P, Poole K (2005) Mutations in PA3574 (nalD) lead to increased MexAB-OprM expression and multidrug resistance in laboratory and clinical isolates of Pseudomonas aeruginosa. Antimicrob Agents Chemother 49:1782–1786CrossRefGoogle Scholar
  19. 19.
    Quale J, Bratu S, Gupta J, Landman D (2006) Interplay of efflux system, ampC, and oprD expression in carbapenem resistance of Pseudomonas aeruginosa clinical isolates. Antimicrob Agents Chemother 50:1633–1641CrossRefGoogle Scholar
  20. 20.
    Dumas JL, Van Delden C, Perron K, Kohler T (2006) Analysis of antibiotic resistance gene expression in Pseudomonas aeruginosa by quantitative real-time-PCR. FEMS Microbiol Lett 254:217–225CrossRefGoogle Scholar
  21. 21.
    Tahmasebi Birgani M, Erfani-Moghadam V, Babaei E, Najafi F, Zamani M, Shariati M, Nazem S, Farhangi B, Motahari P, Sadeghizadeh M (2015) Dendrosomal nano-curcumin; the novel formulation to improve the anticancer properties of curcumin. Progr Biol Sci 5:143–158Google Scholar
  22. 22.
    Niamsa N, Sittiwet C (2009) Antimicrobial activity of curcuma longa aqueous extract. J Pharmacol Toxicol 4:173–177CrossRefGoogle Scholar
  23. 23.
    Ungphaiboon SST, Singchangchai P, Sungkarak S, Rattanasuwan P, Itharat A (2005) Study on antioxidant and antimicrobial activities of turmeric clear liquid soap for wound treatment of HIV patients. Thai Herbs 27:569–578Google Scholar
  24. 24.
    Kim MK, Choi GJ, Lee HS (2003) Fungicidal property of Curcuma longa L. rhizome-derived curcumin against phytopathogenic fungi in a greenhouse. J Agric Food Chem 51:1578–1581CrossRefGoogle Scholar
  25. 25.
    Rahimi HR, Nedaeinia R, Shamloo AS, Nikdoust S, Oskuee RK (2016) Novel delivery system for natural products: nano-curcumin formulations. Avicenna J Phytomed 6:383–398Google Scholar
  26. 26.
    Babaei E, Sadeghizadeh M, Hassan ZM, Feizi MA, Najafi F, Hashemi SM (2012) Dendrosomal curcumin significantly suppresses cancer cell proliferation in vitro and in vivo. Int Immunopharmacol 12:226–234CrossRefGoogle Scholar
  27. 27.
    Esmatabadi MJD, Sarkandi M, Zadeh HM, Khaledi G, Montazeri M, Shekarabi HSZ, Hormoz YA, Asgari EA (2015) Comparative evaluation of curcumin and curcumin loaded- dendrosome nanoparticle effects on the viability of SW480 colon carcinoma and Huh7 hepatoma cells. Res J Pharmacogn 2:9–16Google Scholar
  28. 28.
    Tahmasebi Mirgani M, Isacchi B, Sadeghizadeh M, Marra F, Bilia AR, Mowla SJ, Najafi F, Babaei E (2014) Dendrosomal curcumin nanoformulation downregulates pluripotency genes via miR-145 activation in U87MG glioblastoma cells. Int J Nanomed 9:403–417Google Scholar
  29. 29.
    Liu G, Luo Q, Gao H, Chen Y, Wei X, Dai H, Zhang Z, Ji J (2015) Cell membrane-inspired polymeric micelles as carriers for drug delivery. Biomater Sci 3:490–499CrossRefGoogle Scholar
  30. 30.
    Nardin C, Thoeni S, Widmer J, Winterhalter M, Meier W (2000) Nanoreactors based on (polymerized) ABA-triblock copolymer vesicles. Chem Commun 15:1433–1434CrossRefGoogle Scholar
  31. 31.
    Eshra KA, Shalaby M (2017) Efflux pump inhibition effect of curcumin and phenylalanine arginyl β-naphthylamide (PAβN) against multidrug resistant Pseudomonas aeruginosa isolated from burn infections in Tanta University Hospitals. Egypt J Med Microbiol 26:113–118CrossRefGoogle Scholar
  32. 32.
    Yun DG, Lee DG (2016) Antibacterial activity of curcumin via apoptosis-like response in Escherichia coli. Appl Microbiol Biotechnol 100:5505–5514CrossRefGoogle Scholar
  33. 33.
    Shlar I, Droby S, Choudhary R, Rodov V (2017) The mode of antimicrobial action of curcumin depends on the delivery system: monolithic nanoparticles vs. supramolecular inclusion complex. RSC Adv 7:42559–42569CrossRefGoogle Scholar
  34. 34.
    Ravindran J, Prasad S, Aggarwal BB (2009) Curcumin and cancer cells: how many ways can curry kill tumor cells selectively? AAPS J 11:495–510CrossRefGoogle Scholar
  35. 35.
    Syng-Ai C, Kumari AL, Khar A (2004) Effect of curcumin on normal and tumor cells: role of glutathione and bcl-2. Mol Cancer Ther 3:1101–1108Google Scholar
  36. 36.
    Vallianou NG, Evangelopoulos A, Schizas N, Kazazis C (2015) Potential anticancer properties and mechanisms of action of curcumin. Anticancer Res 35:645–651Google Scholar
  37. 37.
    Lister PD, Wolter DJ, Hanson ND (2009) Antibacterial-resistant Pseudomonas aeruginosa: clinical impact and complex regulation of chromosomally encoded resistance mechanisms. Clin Microbiol Rev 22:582–610CrossRefGoogle Scholar
  38. 38.
    Morita Y, Tomida J, Kawamura Y (2012) MexXY multidrug efflux system of Pseudomonas aeruginosa. Front Microbiol 3:408CrossRefGoogle Scholar
  39. 39.
    Wolter DJ, Smith-Moland E, Goering RV, Hanson ND, Lister PD (2004) Multidrug resistance associated with mexXY expression in clinical isolates of Pseudomonas aeruginosa from a Texas hospital. Diagn Microbiol Infect Dis 50:43–50CrossRefGoogle Scholar
  40. 40.
    Sharma M, Manoharlal R, Shukla S, Puri N, Prasad T, Ambudkar SV, Prasad R (2009) Curcumin modulates efflux mediated by yeast ABC multidrug transporters and is synergistic with antifungals. Antimicrob Agents Chemother 53:3256–3265CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Biology, Faculty of Science, Rasht BranchIslamic Azad UniversityRashtIran
  2. 2.Department of Genetics, Faculty of Biological SciencesTarbiat Modares UniversityTehranIran

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