Comparative Genomics for the Elucidation of Multidrug Resistance in <named-content content-type="genus-species">Candida lusitaniae</named-content>

ABSTRACT Multidrug resistance (MDR) has emerged in hospitals due to the use of several agents administered in combination or sequentially to the same individual. We reported earlier MDR in Candida lusitaniae during therapy with amphotericin B (AmB), azoles, and candins. Here, we used comparative gen...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Abhilash Kannan, Sandra A. Asner, Emilie Trachsel, Steve Kelly, Josie Parker, Dominique Sanglard
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Candida genome analysis antifungal resistance multidrug resistance Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/f8eb420f828c42ef95ad9154fe75822e
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:f8eb420f828c42ef95ad9154fe75822e
record_format	dspace
spelling	oai:doaj.org-article:f8eb420f828c42ef95ad9154fe75822e2021-11-15T15:54:47ZComparative Genomics for the Elucidation of Multidrug Resistance in <named-content content-type="genus-species">Candida lusitaniae</named-content>10.1128/mBio.02512-192150-7511https://doaj.org/article/f8eb420f828c42ef95ad9154fe75822e2019-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02512-19https://doaj.org/toc/2150-7511ABSTRACT Multidrug resistance (MDR) has emerged in hospitals due to the use of several agents administered in combination or sequentially to the same individual. We reported earlier MDR in Candida lusitaniae during therapy with amphotericin B (AmB), azoles, and candins. Here, we used comparative genomic approaches between the initial susceptible isolate and 4 other isolates with different MDR profiles. From a total of 18 nonsynonymous single nucleotide polymorphisms (NSS) in genome comparisons with the initial isolate, six could be associated with MDR. One of the single nucleotide polymorphisms (SNPs) occurred in a putative transcriptional activator (MRR1) resulting in a V668G substitution in isolates resistant to azoles and 5-fluorocytosine (5-FC). We demonstrated by genome editing that MRR1 acted by upregulation of MFS7 (a multidrug transporter) in the presence of the V668G substitution. MFS7 itself mediated not only azole resistance but also 5-FC resistance, which represents a novel resistance mechanism for this drug class. Three other distinct NSS occurred in FKS1 (a glucan synthase gene that is targeted by candins) in three candin-resistant isolates. Last, two other NSS in ERG3 and ERG4 (ergosterol biosynthesis) resulting in nonsense mutations were revealed in AmB-resistant isolates, one of which accumulated the two ERG NSS. AmB-resistant isolates lacked ergosterol and exhibited sterol profiles, consistent with ERG3 and ERG4 defects. In conclusion, this genome analysis combined with genetics and metabolomics helped decipher the resistance profiles identified in this clinical case. MDR isolates accumulated six different mutations conferring resistance to all antifungal agents used in medicine. This case study illustrates the capacity of C. lusitaniae to rapidly adapt under drug pressure within the host. IMPORTANCE Antifungal resistance is an inevitable phenomenon when fungal pathogens are exposed to antifungal drugs. These drugs can be grouped in four distinct classes (azoles, candins, polyenes, and pyrimidine analogs) and are used in different clinical settings. Failures in therapy implicate the sequential or combined use of these different drug classes, which can result in some cases in the development of multidrug resistance (MDR). MDR is particularly challenging in the clinic since it drastically reduces possible treatment alternatives. In this study, we report the rapid development of MDR in Candida lusitaniae in a patient, which became resistant to all known antifungal agents used until now in medicine. To understand how MDR developed in C. lusitaniae, whole-genome sequencing followed by comparative genome analysis was undertaken in sequential MDR isolates. This helped to detect all specific mutations linked to drug resistance and explained the different MDR patterns exhibited by the clinical isolates.Abhilash KannanSandra A. AsnerEmilie TrachselSteve KellyJosie ParkerDominique SanglardAmerican Society for MicrobiologyarticleCandidagenome analysisantifungal resistancemultidrug resistanceMicrobiologyQR1-502ENmBio, Vol 10, Iss 6 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Candida genome analysis antifungal resistance multidrug resistance Microbiology QR1-502
spellingShingle	Candida genome analysis antifungal resistance multidrug resistance Microbiology QR1-502 Abhilash Kannan Sandra A. Asner Emilie Trachsel Steve Kelly Josie Parker Dominique Sanglard Comparative Genomics for the Elucidation of Multidrug Resistance in <named-content content-type="genus-species">Candida lusitaniae</named-content>
description	ABSTRACT Multidrug resistance (MDR) has emerged in hospitals due to the use of several agents administered in combination or sequentially to the same individual. We reported earlier MDR in Candida lusitaniae during therapy with amphotericin B (AmB), azoles, and candins. Here, we used comparative genomic approaches between the initial susceptible isolate and 4 other isolates with different MDR profiles. From a total of 18 nonsynonymous single nucleotide polymorphisms (NSS) in genome comparisons with the initial isolate, six could be associated with MDR. One of the single nucleotide polymorphisms (SNPs) occurred in a putative transcriptional activator (MRR1) resulting in a V668G substitution in isolates resistant to azoles and 5-fluorocytosine (5-FC). We demonstrated by genome editing that MRR1 acted by upregulation of MFS7 (a multidrug transporter) in the presence of the V668G substitution. MFS7 itself mediated not only azole resistance but also 5-FC resistance, which represents a novel resistance mechanism for this drug class. Three other distinct NSS occurred in FKS1 (a glucan synthase gene that is targeted by candins) in three candin-resistant isolates. Last, two other NSS in ERG3 and ERG4 (ergosterol biosynthesis) resulting in nonsense mutations were revealed in AmB-resistant isolates, one of which accumulated the two ERG NSS. AmB-resistant isolates lacked ergosterol and exhibited sterol profiles, consistent with ERG3 and ERG4 defects. In conclusion, this genome analysis combined with genetics and metabolomics helped decipher the resistance profiles identified in this clinical case. MDR isolates accumulated six different mutations conferring resistance to all antifungal agents used in medicine. This case study illustrates the capacity of C. lusitaniae to rapidly adapt under drug pressure within the host. IMPORTANCE Antifungal resistance is an inevitable phenomenon when fungal pathogens are exposed to antifungal drugs. These drugs can be grouped in four distinct classes (azoles, candins, polyenes, and pyrimidine analogs) and are used in different clinical settings. Failures in therapy implicate the sequential or combined use of these different drug classes, which can result in some cases in the development of multidrug resistance (MDR). MDR is particularly challenging in the clinic since it drastically reduces possible treatment alternatives. In this study, we report the rapid development of MDR in Candida lusitaniae in a patient, which became resistant to all known antifungal agents used until now in medicine. To understand how MDR developed in C. lusitaniae, whole-genome sequencing followed by comparative genome analysis was undertaken in sequential MDR isolates. This helped to detect all specific mutations linked to drug resistance and explained the different MDR patterns exhibited by the clinical isolates.
format	article
author	Abhilash Kannan Sandra A. Asner Emilie Trachsel Steve Kelly Josie Parker Dominique Sanglard
author_facet	Abhilash Kannan Sandra A. Asner Emilie Trachsel Steve Kelly Josie Parker Dominique Sanglard
author_sort	Abhilash Kannan
title	Comparative Genomics for the Elucidation of Multidrug Resistance in <named-content content-type="genus-species">Candida lusitaniae</named-content>
title_short	Comparative Genomics for the Elucidation of Multidrug Resistance in <named-content content-type="genus-species">Candida lusitaniae</named-content>
title_full	Comparative Genomics for the Elucidation of Multidrug Resistance in <named-content content-type="genus-species">Candida lusitaniae</named-content>
title_fullStr	Comparative Genomics for the Elucidation of Multidrug Resistance in <named-content content-type="genus-species">Candida lusitaniae</named-content>
title_full_unstemmed	Comparative Genomics for the Elucidation of Multidrug Resistance in <named-content content-type="genus-species">Candida lusitaniae</named-content>
title_sort	comparative genomics for the elucidation of multidrug resistance in <named-content content-type="genus-species">candida lusitaniae</named-content>
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/f8eb420f828c42ef95ad9154fe75822e
work_keys_str_mv	AT abhilashkannan comparativegenomicsfortheelucidationofmultidrugresistanceinnamedcontentcontenttypegenusspeciescandidalusitaniaenamedcontent AT sandraaasner comparativegenomicsfortheelucidationofmultidrugresistanceinnamedcontentcontenttypegenusspeciescandidalusitaniaenamedcontent AT emilietrachsel comparativegenomicsfortheelucidationofmultidrugresistanceinnamedcontentcontenttypegenusspeciescandidalusitaniaenamedcontent AT stevekelly comparativegenomicsfortheelucidationofmultidrugresistanceinnamedcontentcontenttypegenusspeciescandidalusitaniaenamedcontent AT josieparker comparativegenomicsfortheelucidationofmultidrugresistanceinnamedcontentcontenttypegenusspeciescandidalusitaniaenamedcontent AT dominiquesanglard comparativegenomicsfortheelucidationofmultidrugresistanceinnamedcontentcontenttypegenusspeciescandidalusitaniaenamedcontent
_version_	1718427253152415744

Comparative Genomics for the Elucidation of Multidrug Resistance in <named-content content-type="genus-species">Candida lusitaniae</named-content>

Ejemplares similares