We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

In vivo efficacy of pyochelin-mediated delivery of zingerone in Pseudomonas aeruginosa-induced peritonitis

    Surabhi Mangal

    Department of Microbiology, Panjab University, Chandigarh, 160025, India

    ,
    Nishma Ranot

    Department of Microbiology, Panjab University, Chandigarh, 160025, India

    ,
    Anu Nosran

    Department of Microbiology, Panjab University, Chandigarh, 160025, India

    ,
    Vasundhara Singh

    Department of Applied Sciences, Punjab Engineering College (Deemed to be University), Chandigarh, 160012, India

    ,
    Sanjay Chhibber

    Department of Microbiology, Panjab University, Chandigarh, 160025, India

    &
    Kusum Harjai

    *Author for correspondence:

    E-mail Address: kusumharjai1961@gmail.com

    Department of Microbiology, Panjab University, Chandigarh, 160025, India

    Published Online:https://doi.org/10.2217/fmb-2023-0016

    Aim: The efficacy of a pyochelin–zingerone conjugate (PZC) against Pseudomonas aeruginosa in vivo in a mouse model of peritonitis, as well as mode of action in vitro, were investigated. Methods & results: Intraperitoneal administration of PZC (220 mg kg-1 b.wt.) resulted in a significant reduction in bacterial count in liver tissue by 2 log10 on the 4th day post infection. This was supported by reduced levels of inflammatory markers, liver function, inflammatory cytokines and improved histopathology. PZC showed its ability to disrupt the cellular membrane, increase permeability of the membrane and leakage of intracellular contents of P. aeruginosa, resulting in its death. Conclusion: The present study reports the hepatoprotective potential of PZC in an experimental model of P. aeruginosa-induced peritonitis.

    Graphical abstract

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Yang L, Jelsbak L, Marvig RL et al. Evolutionary dynamics of bacteria in a human host environment. Proc. Natl Acad. Sci. USA 108, 7481–7486 (2011).
    • 2. Hancock RE, Speert DP. Antibiotic resistance in Pseudomonas aeruginosa: mechanisms and impact on treatment. Drug Resist. Updat. 3(4), 247–255 (2000).
    • 3. Ghssein G, Matar SF. Chelating mechanisms of transition metals by bacterial metallophores “pseudopaline and staphylopine”: a quantum chemical assessment. Comput. 6(4), 56 (2018).
    • 4. Schalk IJ. A trojan-horse strategy including a bacterial suicide action for the efficient use of a specific Gram-positive antibiotic on Gram-negative bacteria. J. Med. Chem. 61(9), 3842–3844 (2018).
    • 5. Miethke M, Marahiel MA. Siderophore-based iron acquisition and pathogen control. Microbiol. Mol. Biol. Rev. 71(3), 413–451 (2007).
    • 6. Mislin GL, Schalk IJ. Siderophore-dependent iron uptake systems as gates for antibiotic Trojan horse strategies against Pseudomonas aeruginosa. Metallomics 6(3), 408–420 (2014).
    • 7. Raines DJ, Moroz OV, Blagova EV, Turkenburg JP, Wilson KS, Duhme-Klair AK. Bacteria in an intense competition for iron: key component of the Campylobacter jejuni iron uptake system scavenges enterobactin hydrolysis product. Proc. Natl Acad. Sci. USA 113(21), 5850–5855 (2016).
    • 8. Ghssein G, Ezzeddine Z. A review of Pseudomonas aeruginosa metallophores: pyoverdine, pyochelin and pseudopaline. Biology 11(12), 1711 (2022). • This manuscript helped in the introduction and discussion section of the manuscript.
    • 9. Cox CD. Iron uptake with ferri pyochelin and ferric citrate by Pseudomonas aeruginosa. J. Bacteriol. 142(2), 581–587 (1980).
    • 10. Fuchs R, Schafer M, Geoffroy V, Meyer JM. Siderotyping a powerful tool for the characterization of pyoverdines. Curr. Top. Med. Chem. 1(1), 31–57 (2001).
    • 11. Rivault F, Liébert C, Burger A et al. Synthesis of pyochelin–norfloxacin conjugates. Bioorganic Med. Chem. Lett. 17(3), 640–644 (2007).
    • 12. Noël S, Gasser V, Pesset B et al. Synthesis and biological properties of conjugates between fluoroquinolones and a N3″-functionalized pyochelin. Org. Biomol. Chem. 9(24), 8288–8300 (2011). •• Demonstrates the synthesis of nor pyochelin and the conjugation with fluoroquinolones, which is beneficial for the synthesis of the compound.
    • 13. Paulen A, Hoegy F, Roche B, Schalk IJ, Mislin GL. Synthesis of conjugates between oxazolidinone antibiotics and a pyochelin analogue. Bioorganic Med. Chem. Lett. 27(21), 4867–4870 (2017).
    • 14. Mangal S, Dua T, Chauhan M et al. Design, synthesis, and quorum quenching potential of novel catechol–zingerone conjugate to find an elixir to tackle Pseudomonas aeruginosa through the Trojan horse strategy. Front. Chem. 10, 902719 (2022). •• This paper showed the enhanced membrane permeability of catechol-Zingerone conjugate as an elixir against P. aeruginosa which is beneficial for the present manuscript.
    • 15. Kemper KJ. Ginger (Zingiber officinale). Longwood Herbal Task Force 3(1), 1–18 (1999).
    • 16. Nosran A, Kaur P, Randhawa V, Chhibber S, Singh V, Harjai K. Design, synthesis, molecular docking, anti-quorum sensing, and anti-biofilm activity of pyochelin-zingerone conjugate. Drug Dev. Res. 82(4), 605–615 (2021). •• This paper demonstrated the synthesis, antivirulent and antibiofilm potential of the pyochelin–zingerone conjugate (PZC) against P. aeruginosa, which provided fertile grounds for exploring the in vivo efficacy of the PZC.
    • 17. Kumar L, Chhibber S, Harjai K. Zingerone suppresses liver inflammation induced by antibiotic mediated endotoxemia through down regulating hepatic mRNA expression of inflammatory markers in Pseudomonas aeruginosa peritonitis mouse model. PLOS ONE 9(9), e106536 (2014).
    • 18. Anjaneyulu M, Chopra K. Effect of irbesartan on the antioxidant defence system and nitric oxide release in diabetic rat kidney. Am. J. Nephrol. 24(5), 488–496 (2004).
    • 19. Hang L, Haraoka M, Agace WW et al. Macrophage inflammatory protein-2 is required for neutrophil passage across the epithelial barrier of the infected urinary tract. J. Immunol. 162(5), 3037–3044 (1999).
    • 20. Rockett KA, Awburn MM, Rockett EJ, Cowden WB, Clark IA. Possible role of nitric oxide in malarial immunosuppression. Parasite Immunol. 16(5), 243–249 (1994).
    • 21. Vaara M, Vaara T. Outer membrane permeability barrier disruption by polymyxin in polymyxin-susceptible and-resistant Salmonella typhimurium. Antimicrob. Agents Chemother. 19(4), 578–583 (1981).
    • 22. Zhou K, Zhou W, Li P, Liu G, Zhang J, Dai Y. Mode of action of pentocin 31-1: an antilisteria bacteriocin produced by Lactobacillus pentosus from Chinese traditional ham. Food Control. 19(8), 817–822 (2008).
    • 23. Ibrahim JN, Eghnatios E, El Roz A, Fardoun T, Ghssein G. Prevalence, antimicrobial resistance and risk factors for campylobacteriosis in Lebanon. J. Infect. Dev. Ctries. 13(01), 11–20 (2019).
    • 24. Sokhn ES, Salami A, El Roz A, Salloum L, Bahmad HF, Ghssein G. Antimicrobial susceptibilities and laboratory profiles of Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis isolates as agents of urinary tract infection in Lebanon: paving the way for better diagnostics. Med. Sci. 8(3), 32 (2020).
    • 25. Awada R, Ghssein G, El Roz A, Farhat M, Nehme N, Hassan HF. Prevalence of Campylobacter spp. in broilers in North Lebanon. Vet. World 16(2), 322 (2023).
    • 26. Fair RJ, Tor Y. Antibiotics and bacterial resistance in the 21st century. Perspect. Med. Chem. 6(1), 14419–14459 (2014).
    • 27. Prestinaci F, Pezzotti P, Pantosti A. Antimicrobial resistance: a global multifaceted phenomenon. Pathog. Glob. Health. 109(7), 309–318 (2015).
    • 28. Borges A, Abreu AC, Dias C, Saavedra MJ, Borges F, Simões M. New perspectives on the use of phytochemicals as an emergent strategy to control bacterial infections including biofilms. Molecules 21(7), 877 (2016).
    • 29. Mangal S, Singh V, Chhibber S, Harjai K. Natural bioactives versus synthetic antibiotics for the attenuation of quorum sensing-regulated virulence factors of Pseudomonas aeruginosa. Future Microbiol. 17(10), 773–787 (2022). •• Demonstrates the antivirulent potential of plant bioactives including zingerone against Pseudomonas aeruginosa, which is beneficial for the introduction section of the manuscript.
    • 30. Kumar L, Chhibber S, Kumar R, Kumar M, Harjai K. Zingerone silences quorum sensing and attenuates virulence of Pseudomonas aeruginosa. Fitoterapia 102(1), 84–95 (2015).
    • 31. Jannu V, Baddam PG, Boorgula AK, Jambula SR. A review on hepatoprotective plants. Int. J. Drug Dev. Res. 4(3), 1–8 (2012). •• Demonstrates the hepatoprotective potential of plants, which is beneficial for the current manuscript because the agent being employed for conjugation in the present study belongs to category of plant bioactives.
    • 32. Ferreira K, Hu HY, Fetz V et al. Multivalent siderophore–DOTAM conjugates as theranostics for imaging and treatment of bacterial infections. Angew. Chem. Int. Ed. Engl. 56(28), 8272–8276 (2017).
    • 33. Ojo O, Mphahlele MP, Oladeji OS, Mmutlane EM, Ndinteh DT. From wandering weeds to pharmacy: an insight into traditional uses, phytochemicals and pharmacology of genus Chromolaena (Asteraceae). J. Ethnopharmacol. 291, 115155 (2022).
    • 34. Tukov FF, Luyendyk JP, Ganey PE, Roth RA. The role of tumor necrosis factor alpha in lipopolysaccharide/ranitidine-induced inflammatory liver injury. Toxicol. Sci. 100(1), 267–280 (2007).
    • 35. Qiao J, Liu Z, Cui S, Nagy T, Xiong MP. Synthesis and evaluation of an amphiphilic deferoxamine: gallium-conjugated cationic random copolymer against a murine wound healing infection model of Pseudomonas aeruginosa. Acta Biomater. 126(2), 384–393 (2021).
    • 36. Najafzade M, Mosapour A, Nahrevanian H, Zamani Z, Javadian S, Mirkhani F. Effect of trinitroglycerin therapy on serum zinc and copper levels and liver enzyme activities in BALB/c mice infected with Leishmania major MRHO/IR/75/ER. Iran. J. Basic Med. Sci. 18(3), 277 (2015).
    • 37. Li N, Luo M, Fu YJ et al. Effect of corilagin on membrane permeability of Escherichia coli, Staphylococcus aureus and Candida albicans. Phytother. Res. 27(10), 1517–1523 (2013).
    • 38. Chauhan AK, Kang SC. Thymol disrupts the membrane integrity of Salmonella ser. typhimurium in vitro and recovers infected macrophages from oxidative stress in an ex vivo model. Res. Microbiol. 165, 559–565 (2014).
    • 39. Mangal S, Chhibber S, Singh V, Harjai K. Guaiacol augments quorum quenching potential of ciprofloxacin against Pseudomonas aeruginosa. J. Appl. Microbiol. 133(4), 2235–2254 (2022).