Stepwise emergence of azole, echinocandin and amphotericin B multidrug resistance in vivo in Candida albicans orchestrated by multiple genetic alterations
| Autor: | Estella Glintborg Mathiasen, David S. Perlin, Luis Vale Silva, René Jørgensen, Rasmus Hare Jensen, Kristian Fog Nielsen, Maiken Cavling Arendrup, Ghazalel Doroudian, Dominique Sanglard, K. M. T. Astvad |
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| Rok vydání: | 2015 |
| Předmět: |
Microbiology (medical)
Azoles Male Antifungal Agents Echinocandin Genotype Microbial Sensitivity Tests Microbiology 03 medical and health sciences Echinocandins Amphotericin B Drug Resistance Multiple Fungal Candida albicans medicine Animals Humans Pharmacology (medical) DNA Fungal Etest 030304 developmental biology Original Research Aged Pharmacology 0303 health sciences biology Virulence 030306 microbiology Candidiasis Sequence Analysis DNA biology.organism_classification Survival Analysis Corpus albicans 3. Good health Multiple drug resistance Lepidoptera Infectious Diseases Mutation Multilocus sequence typing Amphotericin B/pharmacology Antifungal Agents/pharmacology Azoles/pharmacology Candida albicans/classification Candida albicans/drug effects Candidiasis/drug therapy Candidiasis/microbiology DNA Fungal/chemistry DNA Fungal/genetics Echinocandins/pharmacology Lepidoptera/microbiology Multilocus Sequence Typing Fluconazole medicine.drug |
| Zdroj: | The Journal of antimicrobial chemotherapy Journal of Antimicrobial Chemotherapy, vol. 70, no. 9, pp. 2551-2555 |
| DOI: | 10.1093/jac/dkv140 |
| Popis: | Received 2 April 2015; returned 14 April 2015; revised 22 April 2015; accepted 24 April 2015Objectives:The objective of this study was to characterize the underlying molecular mechanisms in consecutiveclinical Candida albicans isolates from a single patient displaying stepwise-acquired multidrug resistance.Methods: Nine clinical isolates (P-1 to P-9) were susceptibility tested by EUCAST EDef 7.2 and Etest. P-4, P-5, P-7,P-8 and P-9 were available for further studies. Relatedness was evaluated by MLST. Additional genes wereanalysed by sequencing (includingFKS1, ERG11, ERG2 and TAC1) and gene expression by quantitative PCR(CDR1, CDR2 and ERG11). UV-spectrophotometry and GC-MS were used for sterol analyses. In vivo virulencewas determined in the insect model Galleria mellonella and evaluated by log-rank Mantel–Cox tests.Results: P-1+P-2 were susceptible, P-3+P-4 fluconazole resistant, P-5 pan-azole resistant, P-6+P-7 pan-azoleand echinocandin resistant and P-8+P-9 MDR. MLST supported genetic relatedness among clinical isolates. P-4harboured fourchangesinErg11(E266D, G307S, G450EandV488I), increasedexpression ofERG11andCDR2andachange in Tac1 (R688Q).P-5, P-7, P-8 and P-9 had an additional change in Erg11 (A61E), increased expression ofCDR1,CDR2andERG11(except forP-7) and a different aminoacid changein Tac1(R673L). Echinocandin-resistantisolates harboured the Fks1 S645P alteration. Polyene-resistant P-8+P-9 lacked ergosterol and harboured aframeshift mutation in ERG2 (F105SfsX23). Virulence was attenuated (but equivalent) in the clinical isolates,but higher than in the azole- and echinocandin-resistant unrelated control strain.Conclusions: C. albicans demonstrates a diverse capacity to adapt to antifungal exposure. Potentially novelresistance-inducing mutations in TAC1 , ERG11 and ERG2 require independent validation.Keywords: mycology, molecular typing, antifungal resistance, resistance mechanisms |
| Databáze: | OpenAIRE |
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