1887

Abstract

The increase of invasive fungal infections (IFIs) and associated treatment failure in populations at risk is driving us to look for new treatments.

The CIN-102 compound, derived from cinnamon essential oil, could be a new antifungal class with an activity, in particular, on strains resistant to current antifungals but also on biofilms, a factor of virulence and resistance of fungi.

The aim of this study is to show the activity of CIN-102 on various strains resistant to current antifungals, on the biofilm and to determine the possibility of resistance induced with this compound.

We studied the MIC of CIN-102 and of current antifungals (voriconazole and amphotericin B) using CLSI techniques against eight different strains of three genera of filamentous fungi involved in IFIs and having resistance phenotypes to current antifungals. We also determined their effects on biofilm formation, and the induced resistance by voriconazole (VRC) and CIN-102.

MIC values determined for CIN-102 were between 62.5 and 250 µg ml. We demonstrated the antifungal effect of CIN-102 on biofilm, and more particularly on its formation, with 100 % inhibition achieved for most of the strains. CIN-102 at a sub-inhibitory concentration in the medium did not induce resistance in our strains, even after 30 generations.

In this study we show that CIN-102 is effective against resistant filamentous fungi and against biofilm formation. In addition, our strains did not acquire a resistance phenotype against CIN-102 over time, unlike with VRC. CIN-102 is therefore an interesting candidate for the treatment of IFIs, including in cases of therapeutic failure linked to resistance, although further studies on its efficacy, safety and mechanism of action are needed.

Funding
This study was supported by the:
  • SEPTEOS
    • Principle Award Recipient: MaurineD'agostino
  • This is an open-access article distributed under the terms of the Creative Commons Attribution NonCommercial License.
Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.001399
2021-09-07
2024-04-18
Loading full text...

Full text loading...

/deliver/fulltext/jmm/70/9/jmm001399.html?itemId=/content/journal/jmm/10.1099/jmm.0.001399&mimeType=html&fmt=ahah

References

  1. Bitar D, Lortholary O, Le Strat Y, Nicolau J, Coignard B et al. Population-based analysis of invasive fungal infections, France, 2001-2010. Emerg Infect Dis 2014; 20:1149–1155 [View Article] [PubMed]
    [Google Scholar]
  2. Blot M, Lanternier F, Lortholary O. Epidemiology of visceral fungal infection in france and in the world. Rev Prat 2015; 65:1318–1321 [PubMed]
    [Google Scholar]
  3. Rapp RP. Changing strategies for the management of invasive fungal infections. Pharmacotherapy 2004; 24:4S–28S
    [Google Scholar]
  4. Robbins N, Caplan T, Cowen LE. Molecular evolution of antifungal drug resistance. Annu Rev Microbiol 2017; 71:753–775 [View Article] [PubMed]
    [Google Scholar]
  5. Lee HJ, Cho SY, Lee D-G, Park C, Chun HS et al. TR34/L98H mutation in cyp51a gene in Aspergillus fumigatus clinical isolates during posaconazole prophylaxis: First case in Korea. Mycopathologia 2018; 183:731–736 [View Article] [PubMed]
    [Google Scholar]
  6. van der Linden JWM, Camps SMT, Kampinga GA, Arends JPA, Debets-Ossenkopp YJ et al. Aspergillosis due to voriconazole highly resistant Aspergillus fumigatus and recovery of genetically related resistant isolates from domiciles. Clin Infect Dis 2013; 57:513–520 [View Article] [PubMed]
    [Google Scholar]
  7. Donlan RM. Biofilms: microbial life on surfaces. Emerging Infect Dis 2002; 8:881–890 [View Article]
    [Google Scholar]
  8. Chandra J, Kuhn DM, Mukherjee PK, Hoyer LL, McCormick T et al. Biofilm formation by the fungal pathogen Candida albicans: Development, architecture, and drug resistance. J Bacteriol 2001; 183:5385–5394 [View Article] [PubMed]
    [Google Scholar]
  9. LaFleur MD, Kumamoto CA, Lewis K. Candida albicans biofilms produce antifungal-tolerant persister cells. Antimicrob Agents Chemother 2006; 50:3839–3846 [View Article] [PubMed]
    [Google Scholar]
  10. D’agostino M, Tesse N, Frippiat JP, Machouart M, Debourgogne A. Essential oils and their natural active compounds presenting antifungal properties. Molecules 2019; 24: [View Article] [PubMed]
    [Google Scholar]
  11. Mirza Alizadeh A, Golzan SA, Mahdavi A, Dakhili S, Torki Z et al. Recent advances on the efficacy of essential oils on mycotoxin secretion and their mode of action. Crit Rev Food Sci Nutr 20211–26 [View Article] [PubMed]
    [Google Scholar]
  12. Shreaz S, Wani WA, Behbehani JM, Raja V, Irshad M et al. Cinnamaldehyde and its derivatives, a novel class of antifungal agents. Fitoterapia 2016; 112:116–131 [View Article] [PubMed]
    [Google Scholar]
  13. Liang D, Xing F, Selvaraj JN, Liu X, Wang L et al. Inhibitory effect of cinnamaldehyde, citral, and eugenol on aflatoxin biosynthetic gene expression and aflatoxin B1 biosynthesis in Aspergillus flavus. J Food Sci 2015; 80:M2917–24 [View Article] [PubMed]
    [Google Scholar]
  14. Morcia C, Tumino G, Ghizzoni R, Bara A, Salhi N et al. In vitro evaluation of sub-lethal concentrations of plant-derived antifungal compounds on fusaria growth and mycotoxin production. Molecules 2017; 22: [View Article] [PubMed]
    [Google Scholar]
  15. Khan MSA, Ahmad I. Antifungal activity of essential oils and their synergy with fluconazole against drug-resistant strains of Aspergillus fumigatus and Trichophyton rubrum. Appl Microbiol Biotechnol 2011; 90:1083–1094 [View Article] [PubMed]
    [Google Scholar]
  16. D’agostino M, Tesse N, Lavergne RA, Pape PL, Bouchara JP et al. Characterization of the antifungal effect of a plant-based compound, CIN-102, on the main septal filamentous fungi involved in human pathology. J Glob Antimicrob Resist 2021; 25:171–180 [View Article] [PubMed]
    [Google Scholar]
  17. Wayne P. CLSI Document M38-A2 2008
    [Google Scholar]
  18. Sav H, Rafati H, Öz Y, Dalyan-Cilo B, Ener B et al. Biofilm formation and resistance to fungicides in clinically relevant members of the fungal genus fusarium. J Fungi (Basel) 2018; 4: [View Article]
    [Google Scholar]
  19. Kuhn DM, Balkis M, Chandra J, Mukherjee PK, Ghannoum MA. Uses and limitations of the XTT assay in studies of Candida growth and metabolism. J Clin Microbiol 2003; 41:506–508 [View Article] [PubMed]
    [Google Scholar]
  20. Tasse J, Cara A, Saglio M, Villet R, Laurent F. A steam-based method to investigate biofilm. Sci Rep 2018; 8:13040 [View Article]
    [Google Scholar]
  21. D’Agostino M, Lemmet T, Dufay C, Luc A, Frippiat JP et al. Overinduction of CYP51A gene after exposure to azole antifungals provides a first clue to resistance mechanism in Fusarium solani species complex. Microb Drug Resist 2018; 24:768–773 [View Article] [PubMed]
    [Google Scholar]
  22. Kowalski CH, Morelli KA, Schultz D, Nadell CD, Cramer RA. Fungal biofilm architecture produces hypoxic microenvironments that drive antifungal resistance. Proc Natl Acad Sci U S A 2020; 117:22473–22483 [View Article] [PubMed]
    [Google Scholar]
  23. Mukherjee PK, Chandra J. Candida biofilm resistance. Drug Resist Updat 2004; 7:301–309 [View Article] [PubMed]
    [Google Scholar]
  24. Mowat E, Lang S, Williams C, McCulloch E, Jones B et al. Phase-dependent antifungal activity against Aspergillus fumigatus developing multicellular filamentous biofilms. J Antimicrob Chemother 2008; 62:1281–1284 [View Article] [PubMed]
    [Google Scholar]
  25. Seidler MJ, Salvenmoser S, Müller F-M. Aspergillus fumigatus forms biofilms with reduced antifungal drug susceptibility on bronchial epithelial cells. Antimicrob Agents Chemother 2008; 52:4130–4136 [View Article] [PubMed]
    [Google Scholar]
  26. Barchiesi F, Calabrese D, Sanglard D, Falconi Di Francesco L, Caselli F et al. Experimental induction of fluconazole resistance in Candida tropicalis ATCC 750. Antimicrob Agents Chemother 2000; 44:1578–1584 [View Article] [PubMed]
    [Google Scholar]
  27. Grenouillet F, Eglin G, Muret P, Devillard N, Leroy J. In vitro induction of voriconazole resistance in Candida krusei by azole exposure. In Annual ICAAC/IDSA 46th Annual Meeting (Internet) Washington, France: 2008 https://hal.archives-ouvertes.fr/hal-00341443
    [Google Scholar]
  28. Snelders E, Camps SMT, Karawajczyk A, Schaftenaar G, Kema GHJ et al. Triazole fungicides can induce cross-resistance to medical triazoles in Aspergillus fumigatus. PLoS One 2012; 7:e31801 [View Article]
    [Google Scholar]
  29. Papadopoulos CJ, Carson CF, Chang BJ, Riley TV. Role of the MexAB-OprM efflux pump of Pseudomonas aeruginosa in tolerance to tea tree (Melaleuca alternifolia) oil and its monoterpene components terpinen-4-ol, 1,8-cineole, and alpha-terpineol. Appl Environ Microbiol 2008; 74:1932–1935 [View Article] [PubMed]
    [Google Scholar]
  30. Becerril R, Nerín C, Gómez-Lus R. Evaluation of bacterial resistance to essential oils and antibiotics after exposure to oregano and cinnamon essential oils. Foodborne Pathog Dis 2012; 9:699–705 [View Article] [PubMed]
    [Google Scholar]
  31. Piątkowska E, Rusiecka-Ziółkowska J. Influence of essential oils on infectious agents. Adv Clin Exp Med 2016; 25:989–995 [View Article] [PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.001399
Loading
/content/journal/jmm/10.1099/jmm.0.001399
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error