Hazard of agricultural triazole fungicide: Does cyproconazole induce voriconazole resistance in Aspergillus fumigatus isolates?

Document Type : Original Articles

Authors

1 Invasive Fungi Research Center, Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran

2 Department of Medical Mycology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran

3 Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran

4 Department of Medical Laboratory Sciences, Faculty of Medicine, Sari Branch, Islamic Azad University, Sari, Iran

10.18502/cmm.6.4.5329

Abstract

Background and Purpose: The present study aimed to evaluate the effect of cyproconazole, the most used fungicide in Iranian wheat farms, on the induction of voriconazole resistance in Aspergillus fumigatus isolates.
Materials and Methods: A collection of 20 clinical and environmental isolates were selected for investigation of the in vitro activity of fungicides. The minimum inhibitory concentrations (MICs) were determined by the documented broth microdilution method M38-A2 (CLSI, 2008). Induction experiments were performed and the possibly induced isolate(s) were subjected to antifungal susceptibility testing, sequencing of the CYP51A promoter, and full coding gene. Furthermore, CYP51-protein homology modeling and docking modes were evaluated using SWISS-MODEL (https://swissmodel.expasy.org/) and SEESAR software (version 9.1).
Results: Among 10 susceptible isolates, only one strain showed a high MIC value against voriconazole (MIC=4μg/ml) after 25 passages. Nevertheless, sequencing of the CYP51A promoter and full coding gene did not reveal any mutations. Cyproconazole, which has three nitrogen atoms in the aromatic ring, coordinated to the iron atom of heme through a hydrogen bond contact to residue Lys147 present in the active site of the A. fumigates Cyp51 homology model.
Conclusion: Cyproconazole is being applied extensively in wheat farms in Iran. According to the results, cyproconazole may not play a key role in the induction of azole resistance in the isolates through the environmental route. However, the potential ability of the fungicide to induce medically triazole-resistant strains over a long period of application should not be neglected.
 

Keywords

References

1. Alvarez-Moreno C, Lavergne RA, Hagen F, Morio F, Meis JF, Le Pape P. Azole-resistant Aspergillus fumigatus harboring TR 34/L98H, TR 46/Y121F/T289A and TR 53 mutations related to flower fields in Colombia. Sci Rep. 2017; 7:45631.
2. Lelièvre L, Groh M, Angebault C, Maherault AC, Didier E, Bougnoux ME. Azole resistant Aspergillus fumigatus: an emerging problem. Med Mal Infect. 2013; 43(4):139-45.
3. Verweij PE, Snelders E, Kema GH, Mellado E, Melchers WJ. Azole resistance in Aspergillus fumigatus: a side-effect of environmental fungicide use? Lancet Infect Dis. 2009; 9(12):789-95.
4. Enserink M. Farm fungicides linked to resistance in a human pathogen. Washington, D.C: American Association for the Advancement of Science; 2009.
5. Snelders E, Camps SM, Karawajczyk A, Schaftenaar G, Kema GH, Van der Lee HA, et al. Triazole fungicides can induce cross-resistance to medical triazoles in Aspergillus fumigatus. PLoS One. 2012; 7(3):e31801.
6. Van der Linden J, Arendrup M, Warris A, Lagrou K, Pelloux H, Hauser P, et al. Prospective multicenter international surveillance of azole resistance in Aspergillus fumigatus. Emerg Infect Dis. 2015; 21(6):1041-4.
7. Nabili M, Shokohi T, Moazeni M, Khodavaisy S, Aliyali M, Badiee P, et al. High prevalence of clinical and environmental triazole-resistant Aspergillus fumigatus in Iran: is it a challenging issue? J Med Microbiol. 2016; 65(6):468-75.
8. Snelders E, Rijs AJ, Kema GH, Melchers WJ, Verweij PE. Possible environmental origin of resistance of Aspergillus fumigatus to medical triazoles. Appl Environ Microbiol. 2009; 75(12):4053-7.
9. Snelders E, Karawajczyk A, Schaftenaar G, Verweij PE, Melchers WJ. Azole resistance profile of amino acid changes in Aspergillus fumigatus CYP51A based on protein homology modeling. Antimicrob Agents Chemother. 2010; 54(6):2425-30.
10. Natesan SK, Wu W, Cutright J, Chandrasekar P. In vitro–in vivo correlation of voriconazole resistance due to G448S mutation (cyp51A gene) in Aspergillus fumigatus. Diagn Microbiol Infect Dis. 2012; 74(3):272-7.
11. Howard SJ, Webster I, Moore CB, Gardiner RE, Park S, Perlin DS, et al. Multi-azole resistance in Aspergillus fumigatus. Int J Antimicrob Agents. 2006; 28(5):450-3.
12. Verweij PE, Chowdhary A, Melchers WJ, Meis JF. Azole resistance in Aspergillus fumigatus: can we retain the clinical use of mold-active antifungal azoles? Clin Infect Dis. 2015; 62(3):362-8.
13. Le Pape P, Lavergne RA, Morio F, Alvarez-Moreno C. Multiple fungicide-driven alterations in azole-resistant Aspergillus fumigatus, Colombia, 2015. Emerg Infect Dis. 2016; 22(1):156-7.
14. Hagiwara D, Takahashi H, Watanabe A, Takahashi-Nakaguchi A, Kawamoto S, Kamei K, et al. Whole-genome comparison of Aspergillus fumigatus strains serially isolated from patients with aspergillosis. J Clin Microbiol. 2014; 52(12):4202-9.
15. Verweij PE, Denning DW. The challenge of invsive aspergillus. Increasing numbers in diverse patient groups. Int J Infect Dis. 1997; 2(2):61-3.
16. Manavathu EK, Vazquez JA, Chandrasekar PH. Reduced susceptibility in laboratory-selected mutants of Aspergillus fumigatus to itraconazole due to decreased intracellular accumulation of the antifungal agent. Int J Antimicrob Agents.
1999; 12(3):213-9.
17. Cannon RD, Lamping E, Holmes AR, Niimi K, Baret PV, Keniya MV, et al. Efflux-mediated antifungal drug resistance. Clini Microbiol Rev. 2009; 22(2):291-321.
18. Gisi U. Assessment of selection and resistance risk for demethylation inhibitor fungicides in Aspergillus fumigatus in agriculture and medicine: a critical review. Pest Manag Sci. 2014; 70(3):352-64.
19. Tomlin CD. The pesticide manual: a world compendium. Hampshire: British Crop Production Council; 2009.
20. Faria-Ramos I, Farinha S, Neves-Maia J, Tavares PR, Miranda IM, Estevinho LM, et al. Development of cross-resistance by Aspergillus fumigatus to clinical azoles following exposure to prochloraz, an agricultural azole. BMC Microbiol. 2014; 14(1):155.
21. Bowyer P, Denning DW. Environmental fungicides and triazole resistance in Aspergillus. Pest Manag Sci. 2014; 70(2):173-8.
22. Rex JH. Reference method for broth dilution antifungal susceptibility testing of filamentous fungi: approved standard. Wayne: Clinical and Laboratory Standards Institute; 2008.
23. Kano R, Kohata E, Tateishi A, Murayama SY, Hirose D, Shibata Y, et al. Does farm fungicide use induce azole resistance in Aspergillus fumigatus? Sabouraudia. 2014; 53(2):174-7.
24. World Health Organization. Pesticides-Maximum residue limit of pesticides–Cereals. 1st ed. Geneva: World Health Organization; 2016.
25. Badali H, Vaezi A, Haghani I, Yazdanparast SA, Hedayati MT, Mousavi B, et al. Environmental study of azole‐resistant Aspergillus fumigatus with TR34/L98H mutations in the cyp51A gene in Iran. Mycoses. 2013; 56(6):659-63.
26. Moye-Rowley W. Multiple mechanisms contribute to the development of clinically significant azole resistance in Aspergillus fumigatus. Front Microbiol. 2015; 6:70.
Current Medical Mycology
Volume 6, Issue 4
December 2020
Pages 14-19

Files

History

  • Receive Date: 20 April 2020
  • Revise Date: 08 June 2020
  • Accept Date: 22 December 2020
  • Publish Date: 01 December 2020

Share

How to cite

Statistics