Microbiology and Biotechnology Letters (한국미생물·생명공학회지)

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
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Evaluation of Ciclopirox as a Virulence-modifying Agent Against Multidrug Resistant Pseudomonas aeruginosa Clinical Isolates from Egypt

  • Zakaria, Azza S. (Microbiology and Immunology Department, Faculty of Pharmacy, Alexandria University) ;
  • Edward, Eva A. (Microbiology and Immunology Department, Faculty of Pharmacy, Alexandria University) ;
  • Mohamed, Nelly M. (Microbiology and Immunology Department, Faculty of Pharmacy, Alexandria University)
  • Received : 2019.08.08
  • Accepted : 2019.08.20
  • Published : 2019.12.28
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Abstract

Targeting the pathogen viability using drugs is associated with development of drug resistance due to selective pressure. Hence, there is an increased interest in developing agents that target bacterial virulence. In this study, the inhibitory effect of ciclopirox, an antifungal agent with iron chelation potential, on the microbial virulence factors was evaluated in 26 clinical MDR Pseudomonas aeruginosa isolates collected from Alexandria Main University Hospital, a tertiary hospital in Egypt. Treatment with 9 ㎍/ml ciclopirox inhibited the hemolytic activity in 70% isolates, reduced pyocyanin production, decreased protease secretion in 46% isolates, lowered twitching and swarming motility, and decreased biofilm formation by 1.5- to 4.5-fold. The quantitative real-time PCR analysis revealed that treatment with ciclopirox downregulated the expression levels of alkaline protease (aprA) and pyocyanin (phzA1). Ciclopirox is used to treat hematological malignancies and the systemic administration of ciclopirox is reported to have adequate oral absorption with a satisfactory drug safety profile. It is important to calculate the appropriate clinical dose and therapeutic index to reposition ciclopirox from a topical antifungal agent to a promising virulence-modifying agent agent against P. aeruginosa, a problematic Gram-negative pathogen.

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References

  1. Heras B, Scanlon MJ, Martin JL. 2014. Targeting virulence not viability in the search for future antibacterials. Br. J. Clin. Pharmacol. 79: 208-215. https://doi.org/10.1111/bcp.12356
  2. Carlson-Banning KM, Chou A, Liu Z, Hamill RJ, Song Y, Zechiedrich L. 2013. Toward repurposing ciclopirox as an antibiotic against drug-resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae. PLoS One 8: e69646. https://doi.org/10.1371/journal.pone.0069646
  3. Sonthalia S, Agrawal M. 2018. Topical ciclopirox - recalling a forgotten ally in the fight against cutaneous mycoses. EC Microbiology 14: 515-534.
  4. Alnour TMS, Ahmed-Abakur EH. 2017. Multidrug resistant Pseudomonas (P) aeruginosa: medical impact, pathogenicity, resistance mechanisms and epidemiology. JSM Microbiology 5: 1046.
  5. Strateva T, Mitov I. 2011. Contribution of an arsenal of virulence factors to pathogenesis of Pseudomonas aeruginosa infections. Ann. Microbiol. 61: 717-732. https://doi.org/10.1007/s13213-011-0273-y
  6. Gad GF, El-Domany RA, Zaki S, Ashour HM. 2007. Characterization of Pseudomonas aeruginosa isolated from clinical and environmental samples in Minia, Egypt: prevalence, antibiogram and resistance mechanisms. J. Antimicrob. Chemother. 60: 1010-1017. https://doi.org/10.1093/jac/dkm348
  7. Aboushleib HM, Omar HM, Abozahra R, Elsheredy A, Baraka K. 2015. Correlation of quorum sensing and virulence factors in Pseudomonas aeruginosa isolates in Egypt. J. Infect. Dev. Ctries. 9: 1091-1099. https://doi.org/10.3855/jidc.6492
  8. Overhage J, Bains M, Brazas MD, Hancock RE. 2008. Swarming of Pseudomonas aeruginosa is a complex adaptation leading to increased production of virulence factors and antibiotic resistance. J. Bacteriol. 190: 2671-2679. https://doi.org/10.1128/JB.01659-07
  9. van't Wout EF, van Schadewijk A, van Boxtel R, Dalton LE, Clarke HJ, Tommassen J, et al. 2015. Virulence factors of Pseudomonas aeruginosa induce both the unfolded protein and integrated stress responses in airway epithelial cells. PLoS Pathog. 11: e1004946. https://doi.org/10.1371/journal.ppat.1004946
  10. Pereira SG, Rosa AC, Ferreira AS, Moreira LM, Proenca DN, Morais PV, et al. 2014. Virulence factors and infection ability of Pseudomonas aeruginosa isolates from a hydropathic facility and respiratory infections. J. Appl. Microbiol. 116: 1359-1368. https://doi.org/10.1111/jam.12463
  11. Kiska DL, Gilligan PH. 2003. Pseudomonas, pp. 719-728. In Murray PR, Baron EJ, Jorgensen JH, Pfaller MA, Yolken RH (eds.), Manual of Clinical Microbiology, 8th Ed. American Society of Microbiology, Washington, D.C.
  12. Clinical and Laboratory Standards Institute. 2015. Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Fifth Informational Supplement. CLSI document M100-S25. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA.
  13. Clinical and Laboratory Standards Institute. 2006. Performance Standards for Antimicrobial Susceptibility Testing; Sixteenth Informational Supplement. CLSI document M100-S16. Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA.
  14. Ekanayaka SA, McClellan SA, Barrett RP, Kharotia S, Hazlett LD. 2016. Glycyrrhizin reduces HMGB1 and bacterial load in Pseudomonas aeruginosa Keratitis. Invest. Ophthalmol. Vis. Sci. 57: 5799-5809. https://doi.org/10.1167/iovs.16-20103
  15. O'Toole GA, Pratt LA, Watnick PI, Newman DK, Weaver VB, Kolter R. 1999. Genetic approaches to study of biofilms. Methods Enzymol. 310: 91-109. https://doi.org/10.1016/S0076-6879(99)10008-9
  16. Merritt JH, Kadouri DE, O'Toole GA. 2011. Growing and analyzing static biofilms. Curr. Protoc. Microbiol. 22: 1-8.
  17. Quiblier C, Zinkernagel AS, Schuepbach RA, Berger-Bachi B, Senn MM. 2011. Contribution of SecDF to Staphylococcus aureus resistance and expression of virulence factors. BMC Microbiol. 11: 72. https://doi.org/10.1186/1471-2180-11-72
  18. King EO, Ward YM, Raney DE. 1954. Two simple media for the demonstration of pyocyanin and fluorescein. J. Lab. Clin. Med. 44: 301-307.
  19. United States Pharmacopia. 2008. Microbial Limit Tests. pp. 2412- 2745. US Pharmacopeial Convention Inc. 31st Ed. Rockville: 19.
  20. Essar DW, Eberly L, Hadero A, Crawford IP. 1990. Identification and characterization of genes for a second anthranilate synthase in Pseudomonas aeruginosa: interchangeability of the two anthranilate synthases and evolutionary implications. J. Bacteriol. 172: 884-900. https://doi.org/10.1128/jb.172.2.884-900.1990
  21. Essar DW, Eberly L, Han CY, Crawford IP. 1990. DNA sequences and characterization of four early genes of the tryptophan pathway in Pseudomonas aeruginosa. J. Bacteriol. 172: 853-866. https://doi.org/10.1128/jb.172.2.853-866.1990
  22. Rust L, Messing CR, Iglewski BH. 1994. Elastase assays. Methods Enzymol. 235: 554-562. https://doi.org/10.1016/0076-6879(94)35170-8
  23. Rampioni G, Schuster M, Greenberg EP, Zennaro E, Leoni L. 2009. Contribution of the RsaL global regulator to Pseudomonas aeruginosa virulence and biofilm formation. FEMS Microbiol. Lett. 301: 210-217. https://doi.org/10.1111/j.1574-6968.2009.01817.x
  24. Lenz AP, Williamson KS, Pitts B, Stewart PS, Franklin MJ. 2008. Localized gene expression in Pseudomonas aeruginosa biofilms. Appl. Environ. Microbiol. 74: 4463-4471. https://doi.org/10.1128/AEM.00710-08
  25. Jazayeri JA, Nguyen K, Kotsanas D, Schneiders F, Tan C, Jazayeri M, et al. 2016. Comparison of virulence factors in Pseudomonas aeruginosa strains isolated from cystic fibrosis patients. J. Med. Microb. Diagn. 5: 242.
  26. Pfaffl MW. 2001. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29: e45. https://doi.org/10.1093/nar/29.9.e45
  27. Fernandez L, Breidenstein EB, Song D, Hancock RE. 2012. Role of intracellular proteases in the antibiotic resistance, motility, and biofilm formation of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 56: 1128-1132. https://doi.org/10.1128/aac.05336-11
  28. Driscoll JA, Brody SL, Kollef MH. 2007. The epidemiology, pathogenesis and treatment of Pseudomonas aeruginosa infections. Drugs. 67: 351-368. https://doi.org/10.2165/00003495-200767030-00003
  29. Maatallah M, Cheriaa J, Backhrouf A, Iversen A, Grundmann H, Do T, et al. 2011. Population structure of Pseudomonas aeruginosa from five Mediterranean countries: evidence for frequent recombination and epidemic occurrence of CC235. PLoS One 6: e25617. https://doi.org/10.1371/journal.pone.0025617
  30. Woodford N, Wareham DW, Guerra B, Teale C. 2014. Carbapenemase-producing Enterobacteriaceae and non-Enterobacteriaceae from animals and the environment: an emerging public health risk of our own making? J. Antimicrob. Chemother. 69: 287-291. https://doi.org/10.1093/jac/dkt392
  31. Falagas ME, Koletsi PK, Bliziotis IA. 2006. The diversity of definitions of multidrug-resistant (MDR) and pandrug-resistant (PDR) Acinetobacter baumannii and Pseudomonas aeruginosa. J. Med. Microbiol. 55: 1619-1629. https://doi.org/10.1099/jmm.0.46747-0
  32. Abaza A. 2010. Multidrug resistant Pseudomonas aeruginosa in a health care setting in Alexandria. Bulletin of High Institute of Public Health 40: 333-347. https://doi.org/10.21608/jhiph.2010.20608
  33. Mustafa MH, Chalhoub H, Denis O, Deplano A, Vergison A, Rodriguez-Villalobos H, et al. 2016. Antimicrobial susceptibility of Pseudomonas aeruginosa isolated from cystic fibrosis patients in Northern Europe. Antimicrob. Agents Chemother. 60: 6735-6741. https://doi.org/10.1128/AAC.01046-16
  34. Hachem RY, Chemaly RF, Ahmar CA, Jiang Y, Boktour MR, Rjaili GA, et al. 2007. Colistin is effective in treatment of infections caused by multidrug-resistant Pseudomonas aeruginosa in cancer patients. Antimicrob. Agents Chemother. 51: 1905-1911. https://doi.org/10.1128/AAC.01015-06
  35. Falagas ME, Kasiakou SK. 2005. Colistin: the revival of polymyxins for the management of multidrug-resistant Gram-negative bacterial infections. Clin. Infect. Dis. 40: 1333-1341. https://doi.org/10.1086/429323
  36. Brown D. 2015. Antibiotic resistance breakers: can repurposed drugs fill the antibiotic discovery void? Nat. Rev. Drug Discov. 14: 821-832. https://doi.org/10.1038/nrd4675
  37. Jue SG, Dawson GW, Brogden RN. 1985. Ciclopirox olamine 1% cream. A preliminary review of its antimicrobial activity and therapeutic use. Drugs 29: 330-341. https://doi.org/10.2165/00003495-198529040-00002
  38. Subissi A, Monti D, Togni G, Mailland F. 2010. Ciclopirox: recent nonclinical and clinical data relevant to its use as a topical antimycotic agent. Drugs 70: 2133-2152. https://doi.org/10.2165/11538110-000000000-00000
  39. Abrams BB, Hanel H, Hoehler T. 1991. Ciclopirox olamine: a hydroxypyridone antifungal agent. Clin. Dermatol. 9: 471-477. https://doi.org/10.1016/0738-081X(91)90075-V
  40. Korting HC, Grundmann-Kollmann M. 1997. The hydroxypyridones: a class of antimycotics of its own. Mycoses 40: 243-247. https://doi.org/10.1111/j.1439-0507.1997.tb00227.x
  41. Kruse R, Hengstenberg W, Hanel H, Raether W. 1991. Studies for the elucidation of the mode of action of the antimycotic hydroxypyridone compound, rilopirox. Pharmacology 43: 247-255. https://doi.org/10.1159/000138852
  42. Ostroff RM, Vasil AI, Vasil ML. 1990. Molecular comparison of a nonhemolytic and a hemolytic phospholipase C from Pseudomonas aeruginosa. J. Bacteriol. 172: 5915-5923. https://doi.org/10.1128/jb.172.10.5915-5923.1990
  43. Niewerth M, Kunze D, Seibold M, Schaller M, Korting HC, Hube B. 2003. Ciclopirox olamine treatment affects the expression pattern of Candida albicans genes encoding virulence factors, iron metabolism proteins, and drug resistance factors. Antimicrob. Agents Chemother. 47: 1805-1817. https://doi.org/10.1128/AAC.47.6.1805-1817.2003
  44. Fuse K, Fujimura S, Kikuchi T, Gomi K, Iida Y, Nukiwa T, Watanabe A. 2013. Reduction of virulence factor pyocyanin production in multidrug-resistant Pseudomonas aeruginosa. J. Infect. Chemother. 19: 82-88. https://doi.org/10.1007/s10156-012-0457-9
  45. Kipnis E, Sawa T, Wiener-Kronish J. 2006. Targeting mechanisms of Pseudomonas aeruginosa pathogenesis. Med. Mal. Infect. 36: 78-91. https://doi.org/10.1016/j.medmal.2005.10.007
  46. Mihailidou C, Papakotoulas P, Papavassiliou AG, Karamouzis MV. 2018. Superior efficacy of the antifungal agent ciclopirox olamine over gemcitabine in pancreatic cancer models. Oncotarget 9: 10360-10374. https://doi.org/10.18632/oncotarget.23164
  47. Miao EA, Andersen-Nissen E, Warren SE, Aderem A. 2007. TLR5 and Ipaf: dual sensors of bacterial flagellin in the innate immune system. Semin. Immunopathol. 29: 275-288. https://doi.org/10.1007/s00281-007-0078-z
  48. Malapaka VR, Barrese AA, Tripp BC. 2007. High-throughput screening for antimicrobial compounds using a 96-well format bacterial motility absorbance assay. J. Biomol. Screen. 12: 849-854. https://doi.org/10.1177/1087057107304478
  49. Bjarnsholt T, Tolker-Nielsen T, Hoiby N, Givskov M. 2010. Interference of Pseudomonas aeruginosa signalling and biofilm formation for infection control. Expert. Rev. Mol. Med. 12: e11. https://doi.org/10.1017/S1462399410001420
  50. O'May CY, Sanderson K, Roddam LF, Kirov SM, Reid DW. 2009. Iron-binding compounds impair Pseudomonas aeruginosa biofilm formation, especially under anaerobic conditions. J. Med. Microbiol. 58: 765-773. https://doi.org/10.1099/jmm.0.004416-0
  51. Higgins S, Heeb S, Rampioni G, Fletcher MP, Williams P, Camara M. 2018. Differential regulation of the phenazine biosynthetic operons by quorum sensing in Pseudomonas aeruginosa PAO1-N. Front Cell Infect. Microbiol. 8: 252. https://doi.org/10.3389/fcimb.2018.00252
  52. Weir SJ, Patton L, Castle K, Rajewski L, Kasper J, Schimmer AD. 2011. The repositioning of the anti-fungal agent ciclopirox olamine as a novel therapeutic agent for the treatment of haematologic malignancy. J. Clin. Pharm. Ther. 36: 128-134. https://doi.org/10.1111/j.1365-2710.2010.01172.x
  53. Minden MD, Hogge DE, Weir SJ, Kasper J, Webster DA, Patton L, et al. 2014. Oral ciclopirox olamine displays biological activity in a phase I study in patients with advanced hematologic malignancies. Am. J. Hematol. 89: 363-368. https://doi.org/10.1002/ajh.23640