Jérémy Moreau, Thierry Noël, Kévin Point, Frédéric Tewes, Luc Deroche, Jonathan Clarhaut, Valérie Fitton-Ouhabi, Estelle Perraud, Sandrine Marchand, Julien M Buyck, Kévin Brunet
{"title":"Erg11 中携带 F126L 和 L505F 双突变的泛唑抗性 Meyerozyma guilliermondii 克隆分离物。","authors":"Jérémy Moreau, Thierry Noël, Kévin Point, Frédéric Tewes, Luc Deroche, Jonathan Clarhaut, Valérie Fitton-Ouhabi, Estelle Perraud, Sandrine Marchand, Julien M Buyck, Kévin Brunet","doi":"10.1111/myc.13704","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Meyerozyma guilliermondii is a yeast species responsible for invasive fungal infections. It has high minimum inhibitory concentrations (MICs) to echinocandins, the first-line treatment of candidemia. In this context, azole antifungal agents are frequently used. However, in recent years, a number of azole-resistant strains have been described. Their mechanisms of resistance are currently poorly studied.</p><p><strong>Objective: </strong>The aim of this study was consequently to understand the mechanisms of azole resistance in several clinical isolates of M. guilliermondii.</p><p><strong>Methods: </strong>Ten isolates of M. guilliermondii and the ATCC 6260 reference strain were studied. MICs of azoles were determined first. Whole genome sequencing of the isolates was then carried out and the mutations identified in ERG11 were expressed in a CTG clade yeast model (C. lusitaniae). RNA expression of ERG11, MDR1 and CDR1 was evaluated by quantitative PCR. A phylogenic analysis was developed and performed on M. guilliermondii isolates. Lastly, in vitro experiments on fitness cost and virulence were carried out.</p><p><strong>Results: </strong>Of the ten isolates tested, three showed pan-azole resistance. A combination of F126L and L505F mutations in Erg11 was highlighted in these three isolates. Interestingly, a combination of these two mutations was necessary to confer azole resistance. An overexpression of the Cdr1 efflux pump was also evidenced in one strain. Moreover, the three pan-azole-resistant isolates were shown to be genetically related and not associated with a fitness cost or a lower virulence, suggesting a possible clonal transmission.</p><p><strong>Conclusion: </strong>In conclusion, this study identified an original combination of ERG11 mutations responsible for pan-azole-resistance in M. guilliermondii. Moreover, we proposed a new MLST analysis for M. guilliermondii that identified possible clonal transmission of pan-azole-resistant strains. Future studies are needed to investigate the distribution of this clone in hospital environment and should lead to the reconsideration of the treatment for this species.</p>","PeriodicalId":18797,"journal":{"name":"Mycoses","volume":"67 3","pages":"e13704"},"PeriodicalIF":4.1000,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pan-azole-resistant Meyerozyma guilliermondii clonal isolates harbouring a double F126L and L505F mutation in Erg11.\",\"authors\":\"Jérémy Moreau, Thierry Noël, Kévin Point, Frédéric Tewes, Luc Deroche, Jonathan Clarhaut, Valérie Fitton-Ouhabi, Estelle Perraud, Sandrine Marchand, Julien M Buyck, Kévin Brunet\",\"doi\":\"10.1111/myc.13704\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Meyerozyma guilliermondii is a yeast species responsible for invasive fungal infections. It has high minimum inhibitory concentrations (MICs) to echinocandins, the first-line treatment of candidemia. In this context, azole antifungal agents are frequently used. However, in recent years, a number of azole-resistant strains have been described. Their mechanisms of resistance are currently poorly studied.</p><p><strong>Objective: </strong>The aim of this study was consequently to understand the mechanisms of azole resistance in several clinical isolates of M. guilliermondii.</p><p><strong>Methods: </strong>Ten isolates of M. guilliermondii and the ATCC 6260 reference strain were studied. MICs of azoles were determined first. Whole genome sequencing of the isolates was then carried out and the mutations identified in ERG11 were expressed in a CTG clade yeast model (C. lusitaniae). RNA expression of ERG11, MDR1 and CDR1 was evaluated by quantitative PCR. A phylogenic analysis was developed and performed on M. guilliermondii isolates. Lastly, in vitro experiments on fitness cost and virulence were carried out.</p><p><strong>Results: </strong>Of the ten isolates tested, three showed pan-azole resistance. A combination of F126L and L505F mutations in Erg11 was highlighted in these three isolates. Interestingly, a combination of these two mutations was necessary to confer azole resistance. An overexpression of the Cdr1 efflux pump was also evidenced in one strain. Moreover, the three pan-azole-resistant isolates were shown to be genetically related and not associated with a fitness cost or a lower virulence, suggesting a possible clonal transmission.</p><p><strong>Conclusion: </strong>In conclusion, this study identified an original combination of ERG11 mutations responsible for pan-azole-resistance in M. guilliermondii. Moreover, we proposed a new MLST analysis for M. guilliermondii that identified possible clonal transmission of pan-azole-resistant strains. Future studies are needed to investigate the distribution of this clone in hospital environment and should lead to the reconsideration of the treatment for this species.</p>\",\"PeriodicalId\":18797,\"journal\":{\"name\":\"Mycoses\",\"volume\":\"67 3\",\"pages\":\"e13704\"},\"PeriodicalIF\":4.1000,\"publicationDate\":\"2024-03-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Mycoses\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/myc.13704\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"DERMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Mycoses","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/myc.13704","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"DERMATOLOGY","Score":null,"Total":0}
Pan-azole-resistant Meyerozyma guilliermondii clonal isolates harbouring a double F126L and L505F mutation in Erg11.
Background: Meyerozyma guilliermondii is a yeast species responsible for invasive fungal infections. It has high minimum inhibitory concentrations (MICs) to echinocandins, the first-line treatment of candidemia. In this context, azole antifungal agents are frequently used. However, in recent years, a number of azole-resistant strains have been described. Their mechanisms of resistance are currently poorly studied.
Objective: The aim of this study was consequently to understand the mechanisms of azole resistance in several clinical isolates of M. guilliermondii.
Methods: Ten isolates of M. guilliermondii and the ATCC 6260 reference strain were studied. MICs of azoles were determined first. Whole genome sequencing of the isolates was then carried out and the mutations identified in ERG11 were expressed in a CTG clade yeast model (C. lusitaniae). RNA expression of ERG11, MDR1 and CDR1 was evaluated by quantitative PCR. A phylogenic analysis was developed and performed on M. guilliermondii isolates. Lastly, in vitro experiments on fitness cost and virulence were carried out.
Results: Of the ten isolates tested, three showed pan-azole resistance. A combination of F126L and L505F mutations in Erg11 was highlighted in these three isolates. Interestingly, a combination of these two mutations was necessary to confer azole resistance. An overexpression of the Cdr1 efflux pump was also evidenced in one strain. Moreover, the three pan-azole-resistant isolates were shown to be genetically related and not associated with a fitness cost or a lower virulence, suggesting a possible clonal transmission.
Conclusion: In conclusion, this study identified an original combination of ERG11 mutations responsible for pan-azole-resistance in M. guilliermondii. Moreover, we proposed a new MLST analysis for M. guilliermondii that identified possible clonal transmission of pan-azole-resistant strains. Future studies are needed to investigate the distribution of this clone in hospital environment and should lead to the reconsideration of the treatment for this species.
期刊介绍：
The journal Mycoses provides an international forum for original papers in English on the pathogenesis, diagnosis, therapy, prophylaxis, and epidemiology of fungal infectious diseases in humans as well as on the biology of pathogenic fungi.
Medical mycology as part of medical microbiology is advancing rapidly. Effective therapeutic strategies are already available in chemotherapy and are being further developed. Their application requires reliable laboratory diagnostic techniques, which, in turn, result from mycological basic research. Opportunistic mycoses vary greatly in their clinical and pathological symptoms, because the underlying disease of a patient at risk decisively determines their symptomatology and progress. The journal Mycoses is therefore of interest to scientists in fundamental mycological research, mycological laboratory diagnosticians and clinicians interested in fungal infections.
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