Studyof resistance of pathogenic and opportunistic fungi toantimycotics
https://doi.org/10.29326/2304-196X-2022-11-1-20-26
Abstract
The widespread use of antimycotic agents for the treatment of mycoses in humans and animals is of concern to medical and veterinary specialists due to the emergence of resistance of pathogenic and opportunistic fungi to antifungal agents. In recent years, information has been accumulated on the various molecular mechanisms underlying this phenomenon, but in-depth studies are needed to successfully predict resistance in various groups of fungi. To treat and prevent fungal infections several groups of antimycotics are used, where azoles and allylamines are the most frequent ones, which leads to resistance development in pathogenic and opportunistic fungi. The article presents the results of molecular methods identification of azole-resistant Candida albicans isolates and terbinafine-resistant Trichophyton isolates. The analysis of gene ERG11 nucleotide sequences of 10 Candida albicans isolates, recovered from different animal species, enabled the division of phenotypically resistant and susceptible strains, but could not differentiate between the strains, which have dose-dependent resistance to azoles. Study of single nucleotide polymorphisms in gene SQLE, associated with the resistance development to terbinafine in 12 fungal isolates of genus Trichophyton, did not allow grading them by their resistance, which is likely associated with another resistance mechanism, which can be observed in these strains. The results obtained can serve as a basis for the use of molecular methods to characterize fungi of Candida and Trichophyton genera, however, taking into account the biological features of pathogens from different groups it is reasonable to use several significant genome regions or the results of the whole genome sequencing, as well as the gene expression analysis for successful forecasting of potential resistance.
Keywords
About the Authors
A. D. KozlovaRussian Federation
Candidate of Science (Biology), Leading Researcher, Departmentfor Genodiagnostics of Infectious Animal Diseases of VGNKI Department of Biotechnology,
Moscow
S. P. Yatsentyuk
Russian Federation
Candidate of Science (Biology), Head of the Department for Genodiagnostics of Infectious Animal Diseases of VGNKI, Department of Biotechnology,
Moscow
V. V. Sokolov
Russian Federation
Post-Graduate Student, Research, Department of Mycology,
Moscow
M. G. Manoyan
Russian Federation
Candidate of Sciences (Veterinary Medicine), Head of the Department of Mycology,
Moscow
References
1. Cowen L. E. The evolution of fungal drug resistance: modulating the trajectory from genotype to phenotype. Nat. Rev. Microbiol. 2008; 6 (3): 187–198. DOI: 10.1038/nrmicro1835.
2. Antonovics J., Abbate J. L., Baker C. H., Daley D., Hood M. E., Jenkins C. E., et al. Evolution by any other name: antibiotic resistance and avoidance of the E-word. PLoS Biol. 2007; 5 (2):e30. DOI: 10.1371/journal.pbio.0050030.
3. Sahoo A. K., Mahajan R. Management of tinea corporis, tinea cruris, and tinea pedis: A comprehensive review. Indian Dermatol. Online J. 2016; 7 (2): 77–86. DOI: 10.4103/2229-5178.178099.
4. Odds F. C., Brown A. J., Gow N. A. Antifungal agents: mechanisms of action. Trends Microbiol. 2003; 11 (6): 272–279. DOI: 10.1016/s0966-842x(03)00117-3.
5. Morio F., Loge C., Besse B., Hennequin C., Pape L. P. Screening for amino acid substitutions in the Candida albicans Erg11 protein of azole-susceptible and azole-resistant clinical isolates: new substitutions and a review of the literature. Diagn. Microbiol. Infect. Dis. 2010; 66 (4): 373–384. DOI: 10.1016/j.diagmicrobio.2009.11.006.
6. Casalinuovo I. A., Di Francesco P., Garaci E. Fluconazole resistance in Candida albicans: A review of mechanisms. Eur. Rev. Med. Pharmacol. Sci. 2004; 8 (2): 69–77. PMID: 15267120.
7. White T. C. Increased mRNA levels of ERG16, CDR, and MDR1 correlate with increases in azole resistance in Candida albicans isolates from a patient infected with human immunodeficiency virus. Antimicrob. Agents Chemother. 1997; 41 (7): 1482–1487. DOI: 10.1128/AAC.41.7.1482.
8. Franz R., Kelly S. L., Lamb D. C., Kelly D. E., Ruhnke M., Morschhauser J. Multiple molecular mechanisms contribute to a stepwise development of fluconazole resistance in clinical Candida albicans strains. Antimicrob. Agents Chemother. 1998; 42 (12): 3065–3072. DOI: 10.1128/AAC.42.12.3065.
9. Perea S., Lopez-Ribot J. L., Kirkpatrick W. R., McAtee R. K., Santillan R. A., Martinez M., et al. Prevalence of molecular mechanisms of resistance to azole antifungal agents in Candida albicans strains displaying high-level fluconazole resistance isolated from human immunodeficiency virus-infected patients. Antimicrob. Agents Chemother. 2001; 45 (10): 2676–2684. DOI: 10.1128/AAC.45.10.2676-2684.2001.
10. Barchiesi F., Calabrese D., Sanglard D., Falconi Di Francesco L., Caselli F., Giannini D., Giacometti A., et al. Experimental induction of fluconazole resistance in Candida tropicalis ATCC 750. Antimicrob. Agents Chemother. 2000; 44 (6): 1578–1584. DOI: 10.1128/AAC.44.6.1578-1584.2000.
11. Redding S. W., Kirkpatrick W. R., Coco B. .J, Sadkowski L., Fothergill A. W., Rinaldi M. G., et al. Candida glabrata oropharyngeal candidiasis in patients receiving radiation treatment for head and neck cancer. J. Clin. Microbiol. 2002; 40 (5): 1879–1881. DOI: 10.1128/JCM.40.5.1879-1881.2002.
12. Vandeputte P., Larcher G., Berges T., Renier G., Chabasse D., Bouchara J. P. Mechanisms of azole resistance in a clinical isolate of Candida tropicalis. Antimicrob. Agents Chemother. 2005; 49 (11): 4608–4615. DOI: 10.1128/ AAC.49.11.4608-4615.2005.
13. Rogers P. D., Vermitsky J. P., Edlind T. D., Hilliard G. M. Proteomic analysis of experimentally induced azole resistance in Candida glabrata. J. Antimicrob. Chemother. 2006; 58 (2): 434–438. DOI: 10.1093/jac/dkl221.
14. Jiang C., Dong D., Yu B., Cai G., Wang X., Ji Y., Peng Y. Mechanisms of azole resistance in 52 clinical isolates of Candida tropicalis in China. J. Antimicrob. Chemother. 2013; 68 (4): 778–785. DOI: 10.1093/jac/dks481.
15. Cowen L. E., Sanglard D., Howard S. J., Rogers P. D., Perlin D. S. Mechanisms of antifungal drug resistance. Cold Spring Harb. Perspect. Med. 2014; 5 (7):a019752. DOI: 10.1101/cshperspect.a019752.
16. Selmecki A., Forche A., Berman J. Genomic plasticity of the human fungal pathogen Candida albicans. Eukaryot. Cell. 2010; 9 (7): 991–1008. DOI: 10.1128/EC.00060-10.
17. Harrison B. D., Hashemi J., Bibi M., Pulver R., Bavli D., Nahmias Y., et al. A tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole. PLoS Biol. 2014; 12 (3):e1001815. DOI: 10.1371/journal.pbio.1001815.
18. Favre B., Ryder N. S. Characterization of squalene epoxidase activity from the dermatophyte Trichophyton rubrum and its inhibition by terbinafine and other antimycotic agents. Antimicrob. Agents Chemother. 1996; 40 (2): 443–447. DOI: 10.1128/AAC.40.2.443.
19. Martinez-Rossi N. M., Bitencourt T. A., Peres N. T. A., Lang E. A. S., Gomes E. V., Quaresemin N. R., et al. Dermatophyte resistance to antifungal drugs: Mechanisms and prospectus. Front. Microbiol. 2018; 9:1108. DOI: 10.3389/fmicb.2018.01108.
20. Yamada T., Maeda M., Alshahni M. M., Tanaka R., Yaguchi T., Bontems O., et al. Terbinafine resistance of Trichophyton clinical isolates caused by specific point mutations in the squalene epoxidase gene. Antimicrob. Agents Chemother. 2017; 61 (7):e00115-17. DOI: 10.1128/AAC.00115-17.
21. Saunte D. M. L., Hare R. K., Jørgensen K. M., Jørgensen R., Deleuran M., Zachariae C. O., et al. Emerging terbinafine resistance in Trichophyton: Clinical characteristics, squalene epoxidase gene mutations, and a reliable EUCAST method for detection. Antimicrob. Agents Chemother. 2019; 63 (10):e01126-19. DOI: 10.1128/AAC.01126-19.
22. Arendrup M. C., Meletiadis J., Mouton J. W., Lagrou K., Hamal P., et al. EUCAST Definitive Document E.Def 7.3.2: Method for the determination of broth dilution minimum inhibitory concentrations of antifungal agents for yeasts. 2020. Available at: http://www.eucast.org.
23. The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs for antifungal agents, version 10.0. 2020. Available at: http://www.eucast.org/astoffungi/clinicalbreakpointsforantifungals.
24. Manoyan M., Sokolov V., Gursheva A., Gabuzyan N., Panin A. P034. Sensitivity of isolated dermatophyte strains to antifungal drugs in the Russian Federation. In: 9th Trends in Medical Mycology Held on 11–14 October 2019, Nice, France, Organized under the Auspices of EORTC-IDG and ECMM. J. Fungi. 2019; 5 (4):95. DOI: 10.3390/jof5040095.
25. Lee M.-K., Williams L. E., Warnock D. W., Arthington-Skaggs B. A. Drug resistance genes and trailing growth in Candida albicans isolates. J. Antimicrob. Chemother. 2004; 53 (2): 217–224. DOI: 10.1093/jac/dkh040.
26. Marichal P., Koymans L., Willemsens S., Bellens D., Verhasselt P., Luyten W., et al. Contribution of mutations in the cytochrome P450 14α-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans. Microbiology (Reading). 1999; 145 (Pt 10): 2701–2713. DOI: 10.1099/00221287-145-10-2701.
27. MacCallum D. M., Coste A., Ischer F., Jacobsen M. D., Odds F. C., Sanglard D. Genetic dissection of azole resistance mechanisms in Candida albicans and their validation in a mouse model of disseminated infection. Antimicrob. Agents Chemother. 2010; 54 (4): 1476–1483. DOI: 10.1128/AAC.01645-09.
Review
For citations:
Kozlova A.D., Yatsentyuk S.P., Sokolov V.V., Manoyan M.G. Studyof resistance of pathogenic and opportunistic fungi toantimycotics. Veterinary Science Today. 2022;11(1):20-26. https://doi.org/10.29326/2304-196X-2022-11-1-20-26