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Demonstration of the efficacy of curcumin on carbapenem-resistant Pseudomonas aeruginosa with Galleria mellonella larvae model

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Abstract

Due to increasing antimicrobial resistance, studies where new treatment options are investigated along with the synergistic effects of natural products with antibiotics have arisen. Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen and infection with multi-drug resistant (MDR) P. aeruginosa poses a critical problem during treatment. Curcumin (CUR) is listed in the literature as one of the promising natural ingredients with its strong antimicrobial activity. In our study, our aim was to investigate the in vitro synergistic effect of CUR with imipenem (IMP) and Colistin (CST) in MDR P. aeruginosa isolates and in vivo activity on Galleria mellonella (G. mellonella) larvae. Three clinical isolates of MDR P. aeruginosa, which were determined to be phenotypically resistant to carbapenems, were used, and KPC and OXA48 resistance genes were determined by PCR method. The synergistic effect of CUR with antibiotics were investigated by the checkerboard method. Larval survival and bacterial load were compared with the in vivo study. In this study, IMP MIC values were significantly reduced (two to eight-fold decrease) in the presence of CUR, and partial synergy was observed. For CST, this value decreased two-fold. Bacterial load was evaluated to investigate the effect of antimicrobials during infection. While the CFUs increased over time in non-treated larvae as compared to the initial inoculum, bacterial load was significantly decreased for the groups treated with CUR, IMP and CST compared to the untreated group (p < 0.05). It was concluded CUR-antibiotic combinations can provide an alternative approach in the treatment of infections with MDR bacteria.

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References

  • Adamczak A, Ożarowski M, Karpiński TM (2020) Curcumin, a natural antimicrobial agent with strain-specific activity. Pharmaceuticals 13:153

    Article  CAS  PubMed Central  Google Scholar 

  • Adamson DH, Krikstopaityte V, Coote PJ (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

    Article  CAS  PubMed  Google Scholar 

  • Al-Wrafy F, Brzozowska E, Górska S, Gamian A (2017) Pathogenic factors of Pseudomonas aeruginosa-the role of biofilm in pathogenicity and as a target for phage therapy. Postepy Hig Med Dosw 71:78–91

    Article  Google Scholar 

  • Ali DO, Nagla MM (2020) Molecular detection of bla OXA-48 gene encoding carbapenem resistance pseudomonas aeruginosa clinical isolates from Khartoum State Hospitals, Sudan. medRxiv 79:101

    Google Scholar 

  • Aloush V, Navon-Venezia S, Seigman-Igra Y, Cabili S, Carmeli Y (2006) Multidrug-resistant Pseudomonas aeruginosa: risk factors and clinical impact. Antimicrob Agents Chemother 50:43–48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Azam MW, Khan AU (2019) Updates on the pathogenicity status of Pseudomonas aeruginosa. Drug Discov Today 24:350–359

    Article  CAS  PubMed  Google Scholar 

  • 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. https://doi.org/10.4172/2472-1212.1000116

    Article  Google Scholar 

  • Barnoy S, Gancz H, Zhu Y, Honnold CL, Zurawski DV, Venkatesan MM (2017) The Galleria mellonella larvae as an in vivo model for evaluation of Shigella virulence. Gut Microbes 8:335–350

    Article  PubMed  PubMed Central  Google Scholar 

  • Brunton LL, Knollmann BC, Hilal-Dandan RG (2018) Gilman’s the pharmacological basis of therapeutics. McGraw-hill Education, New York

    Google Scholar 

  • Bugli F et al (2018) Curcumin-loaded graphene oxide flakes as an effective antibacterial system against methicillin-resistant Staphylococcus aureus. Interface Focus 8:20170059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bush K (2018) Past and present perspectives on β-lactamases. Antimicrob Agents Chemother 62:e01076–e01118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carmeli Y, Troillet N, Karchmer AW, Samore MH (1999) Health and economic outcomes of antibiotic resistance in Pseudomonas aeruginosa. Arch Intern Med 159:1127–1132

    Article  CAS  PubMed  Google Scholar 

  • Curran CS, Bolig T, Torabi-Parizi P (2018) Mechanisms and targeted therapies for Pseudomonas aeruginosa lung infection. Am J Respir Crit Care Med 197:708–727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dai C, Wang Y, Sharma G, Shen J, Velkov T, Xiao X (2020) Polymyxins–curcumin combination antimicrobial therapy: safety implications and efficacy for infection treatment. Antioxidants 9:506

    Article  CAS  PubMed Central  Google Scholar 

  • Dimatatac EL, Alejandria MM, Montalban C, Pineda C, Ang C, Delino R (2003) Clinical outcomes and costs of care of antibiotic resistant Pseudomonas aeruginosa infections. Philipp J Microbiol Infect Dis 32:159–167

    Google Scholar 

  • Dwivedi GR et al (2021) Drug resistance reversal potential of multifunctional thieno [3, 2-c] pyran via potentiation of antibiotics in MDR P. aeruginosa. Biomed Pharmacother 142:112084

    Article  CAS  PubMed  Google Scholar 

  • Falagas ME, Kasiakou SK, Saravolatz LD (2005) Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis 40:1333–1341

    Article  CAS  PubMed  Google Scholar 

  • Francis C, Eric D (2017) Carbapenem resistance: a review. Med Sci 6:1

    Google Scholar 

  • Gellatly SL, Hancock RE (2013) Pseudomonas aeruginosa: new insights into pathogenesis and host defenses. Pathog Dis 67:159–173

    Article  CAS  PubMed  Google Scholar 

  • Gülen D, Şafak B, Erdal B, Günaydın B (2021) Curcumin-meropenem synergy in carbapenem resistant Klebsiella pneumoniae curcumin-meropenem synergy. Iran J Microbiol 13:345

    PubMed  PubMed Central  Google Scholar 

  • Gupta SC, Patchva S, Aggarwal BB (2013) Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J 15:195–218

    Article  CAS  PubMed  Google Scholar 

  • Gurung S et al (2020) Detection of OXA-48 gene in carbapenem-resistant Escherichia coli and Klebsiella pneumoniae from urine samples. Infect Drug Resist 13:2311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hancock RE, Brinkman FS (2002) Function of Pseudomonas porins in uptake and efflux. Annu Rev Microbiol 56:17–38

    Article  CAS  PubMed  Google Scholar 

  • Hashemi AB, Nakhaei Moghaddam M, Forghanifard MM, Yousefi E (2021) Detection of blaOXA-10 and blaOXA-48 genes in Pseudomonas aeruginosa clinical isolates by multiplex PCR. J Med Microbiol Infect Dis 9:142–147

    CAS  Google Scholar 

  • Hemaiswarya S, Kruthiventi AK, Doble M (2008) Synergism between natural products and antibiotics against infectious diseases. Phytomedicine 15:639–652

    Article  CAS  PubMed  Google Scholar 

  • Hewlings SJ, Kalman DS (2017) Curcumin: a review of its effects on human health. Foods 6:92

    Article  PubMed Central  CAS  Google Scholar 

  • Hussain Y et al (2022) Antimicrobial potential of curcumin: therapeutic potential and challenges to clinical applications. Antibiotics 11:322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • ISO (2006) Clinical laboratory testing and in vitro diagnostic test systems—susceptibility testing of infectious agents and evaluation of performance of antimicrobial susceptibility test devices—part 1: reference method for testing the in vitro activity of antimicrobial agents against rapidly growing aerobic bacteria involved in infectious diseases

  • Itzia Azucena RC et al (2019) Drug susceptibility testing and synergistic antibacterial activity of curcumin with antibiotics against enterotoxigenic Escherichia coli. Antibiotics (basel) 8:43. https://doi.org/10.3390/antibiotics8020043

    Article  CAS  Google Scholar 

  • Kali A, Devaraj Bhuvaneshwar P, Charles M, Seetha KS (2016) Antibacterial synergy of curcumin with antibiotics against biofilm producing clinical bacterial isolates. J Basic Clin Pharm 7:93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaur A, Sharma P, Capalash N (2018) Curcumin alleviates persistence of Acinetobacter baumannii against colistin. Sci Rep 8:1–11

    Google Scholar 

  • Khalifa ABH, Moissenet D, Thien HV, Khedher M (2011) Les facteurs de virulence de Pseudomonas aeruginosa: mécanismes et modes de régulations. Ann Biol Clin 69:393–403

    Google Scholar 

  • Krezdorn J, Adams S, Coote PJ (2014) 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 63:945–955

    Article  PubMed  Google Scholar 

  • Laishram S et al (2016) Determination of synergy between sulbactam, meropenem and colistin in carbapenem-resistant Klebsiella pneumoniae and Acinetobacter baumannii isolates and correlation with the molecular mechanism of resistance. J Chemother 28:297–303

    Article  CAS  PubMed  Google Scholar 

  • Lister PD, Wolter DJ, Hanson ND (2009) Antibacterial-resistant Pseudomonas aeruginosa: clinical impact and complex regulation of chromosomally encoded resistance mechanisms. Clin Microbiol Rev 22:582–610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Livermore DM (2002) Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare? Clin Infect Dis 34:634–640

    Article  CAS  PubMed  Google Scholar 

  • Magiorakos A-P et al (2012) Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 18:268–281

    Article  CAS  PubMed  Google Scholar 

  • Malmquist JA, Rogan MR, McGillivray SM (2019) Galleria mellonella as an infection model for Bacillus anthracis sterne. Front Cell Infect Microbiol 9:360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ménard G, Rouillon A, Ghukasyan G, Emily M, Felden B, Donnio P-Y (2021) Galleria mellonella larvae as an infection model to investigate sRNA-mediated pathogenesis in Staphylococcus aureus. Front Cell Infect Microbiol. https://doi.org/10.3389/fcimb.2021.631710

    Article  PubMed  PubMed Central  Google Scholar 

  • Mesa-Arango AC, Forastiero A, Bernal-Martínez L, Cuenca-Estrella M, Mellado E, Zaragoza O (2013) The non-mammalian host Galleria mellonella can be used to study the virulence of the fungal pathogen Candida tropicalis and the efficacy of antifungal drugs during infection by this pathogenic yeast. Med Mycol 51:461–472

    Article  CAS  PubMed  Google Scholar 

  • Micek ST, Lloyd AE, Ritchie DJ, Reichley RM, Fraser VJ, Kollef MH (2005) Pseudomonas aeruginosa bloodstream infection: importance of appropriate initial antimicrobial treatment. Antimicrob Agents Chemother 49:1306–1311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mun S-H et al (2013) Synergistic antibacterial effect of curcumin against methicillin-resistant Staphylococcus aureus. Phytomedicine 20:714–718

    Article  CAS  PubMed  Google Scholar 

  • Nation RL, Li J (2009) Colistin in the 21st century. Curr Opin Infect Dis 22:535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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. https://doi.org/10.7860/JCDR/2014/8329.4965

    Article  PubMed  PubMed Central  Google Scholar 

  • Nicolau DP (2008) Carbapenems: a potent class of antibiotics. Expert Opin Pharmacother 9:23–37

    Article  CAS  PubMed  Google Scholar 

  • Peleg AY, Adams J, Paterson DL (2007) Tigecycline efflux as a mechanism for nonsusceptibility in Acinetobacter baumannii. Antimicrob Agents Chemother 51:2065–2069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Poirel L, Walsh TR, Cuvillier V, Nordmann P (2011) Multiplex PCR for detection of acquired carbapenemase genes. Diagn Microbiol Infect Dis 70:119–123

    Article  CAS  PubMed  Google Scholar 

  • Rocha AJ, Barsottini MRdO, Rocha RR, Laurindo MV, Moraes FLLd, Rocha SLd (2019) Pseudomonas aeruginosa: virulence factors and antibiotic resistance genes. Braz Arch Biol Technol. https://doi.org/10.1590/1678-4324-2019180503

    Article  Google Scholar 

  • Rossi E, Ghoul M, La Rosa R (2022) Pseudomonas aeruginosa Pathogenesis: Virulence, Antibiotic Tolerance and Resistance, Stress Responses and Host-Pathogen Interactions. Frontiers in Cellular and Infection Microbiology 12

  • Sakyo S, Tomita H, Tanimoto K, Fujimoto S, Ike Y (2006) Potency of carbapenems for the prevention of carbapenem-resistant mutants of Pseudomonas aeruginosa. J Antibiot 59:220–228

    Article  CAS  Google Scholar 

  • Sardi JdCO et al (2017) Antibacterial activity of diacetylcurcumin against Staphylococcus aureus results in decreased biofilm and cellular adhesion. J Med Microbiol 66:816–824

    Article  CAS  PubMed  Google Scholar 

  • 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 2014:561456

    Article  PubMed  PubMed Central  Google Scholar 

  • Sharahi JY et al (2020) In vitro antibacterial activity of curcumin-meropenem combination against extensively drug-resistant (XDR) bacteria isolated from burn wound infections. Avicenna J Phytomed 10:3

    CAS  Google Scholar 

  • Timurkaynak F, Can F, Azap ÖK, Demirbilek M, Arslan H, Karaman SÖ (2006) In vitro activities of non-traditional antimicrobials alone or in combination against multidrug-resistant strains of Pseudomonas aeruginosa and Acinetobacter baumannii isolated from intensive care units. Int J Antimicrob Agents 27:224–228

    Article  CAS  PubMed  Google Scholar 

  • 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:e0121313

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tzouvelekis L, Markogiannakis A, Piperaki E, Souli M, Daikos G (2014) Treating infections caused by carbapenemase-producing Enterobacteriaceae. Clin Microbiol Infect 20:862–872

    Article  CAS  PubMed  Google Scholar 

  • Velikova N, Kavanagh K, Wells JM (2016) Evaluation of Galleria mellonella larvae for studying the virulence of Streptococcus suis. BMC Microbiol 16:1–9

    Article  CAS  Google Scholar 

  • Verma N, Prahraj A, Mishra B, Behera B, Gupta K (2019) Detection of carbapenemase-producing Pseudomonas aeruginosa by phenotypic and genotypic methods in a tertiary care hospital of East India. J Lab Physicians 11:287–291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Lu Z, Wu H, Lv F (2009) Study on the antibiotic activity of microcapsule curcumin against foodborne pathogens. Int J Food Microbiol 136:71–74

    Article  CAS  PubMed  Google Scholar 

  • WHO I (2017) Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. WHO 2017:1–7

    Google Scholar 

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Acknowledgements

I would like to thank Prof.Dr.Meryem Akpolat Ferah, who provided me with CUR in this study, and Biostatistics faculty member, Dr.Fürüzan Köktürk, who provided the control of statistics.

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The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Zonguldak Bulent Ecevit University, 67100, Zonguldak, Turkey

    Sukran Ozturk

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  1. Sukran Ozturk
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Contributions

Conceptualization, S.O. methodology, S.O. software, S.O.; validation S.O. formal analysis, S.O. statistical analysis,S.O.,F.K investigation, S.O., resources, S.O.; data curation, S.O.; writing—original draft preparation, writing—review and editing, S.O., B.K., visualization, S.O.,supervision, S.O., All authors have read and agreed to the published version of the manuscript.

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Correspondence to Sukran Ozturk.

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Communicated by Erko Stackebrandt.

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Ozturk, S. Demonstration of the efficacy of curcumin on carbapenem-resistant Pseudomonas aeruginosa with Galleria mellonella larvae model. Arch Microbiol 204, 524 (2022). https://doi.org/10.1007/s00203-022-03135-x

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