Reduced Susceptibility to Azoles in Cryptococcus gattii Correlates with the Substitution R258L in a Substrate Recognition Site of the Lanosterol 14-α-Demethylase

Silvia Katherine Carvajal; Javier Melendres; Patricia Escandón; Carolina Firacative

doi:10.1128/spectrum.01403-23

Reduced Susceptibility to Azoles in Cryptococcus gattii Correlates with the Substitution R258L in a Substrate Recognition Site of the Lanosterol 14-α-Demethylase

Silvia Katherine Carvajal, Javier Melendres, Patricia Escandón, Carolina Firacative

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Resumen

Cryptococcus neoformans y Cryptococcus gattii causan la criptococosis, una infección fúngica potencialmente mortal que afecta sobre todo a pacientes inmunodeprimidos. De hecho, la meningitis criptocócica es responsable de alrededor del 19% de las muertes relacionadas con el SIDA en el mundo. Debido a las terapias a largo plazo con azoles para tratar esta micosis, desde hace tiempo se ha informado de resistencias al fluconazol que conducen al fracaso del tratamiento y a un mal pronóstico para ambas especies fúngicas. Entre los mecanismos implicados en la resistencia a los azoles, se han descrito mutaciones en el gen ERG11, que codifica la enzima diana de los azoles lanosterol 14-a-demetilasa. Este estudio tuvo como objetivo establecer la composición aminoacídica del ERG11 de aislados clínicos colombianos de C. neoformans y C. gattii y correlacionar cualquier posible sustitución con el perfil de susceptibilidad in vitro de los aislados a fluconazol, voriconazol e itraconazol. Los resultados de las pruebas de susceptibilidad antifúngica mostraron que los aislados de C. gattii son menos susceptibles a los azoles que los aislados de C. neoformans, lo que podría correlacionarse con las diferencias en la composición de aminoácidos y la estructura del ERG11 de cada especie. Además, en un aislado de C. gattii con CMI elevadas para fluconazol (64 mg/mL) y voriconazol (1 mg/mL), se identificó una mutación G973T que da lugar a la sustitución R258L, localizada en el sitio de reconocimiento de sustrato 3 de ERG11. Este hallazgo sugiere la asociación de la nueva sustitución con el fenotipo de resistencia a los azoles en C. gattii. Se necesitan más investigaciones para determinar el papel exacto que desempeña R258L en la disminución de la susceptibilidad a fluconazol y voriconazol, así como para determinar la participación de mecanismos adicionales de resistencia a fármacos azólicos.

Idioma original	Inglés estadounidense
Número de artículo	e0140323
Páginas (desde-hasta)	1-11
Número de páginas	11
Publicación	Microbiology spectrum
Volumen	11
N.º	4
Fecha en línea anticipada	jun. 21 2023
DOI	https://doi.org/10.1128/spectrum.01403-23
Estado	Publicada - ago. 17 2023

Áreas temáticas de ASJC Scopus

Fisiología
Ecología
Inmunología y Microbiología General
Genética
Microbiología (médica)
Biología celular
Enfermedades infecciosas

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@article{b31966538d4c478e8d58ee8f2d52dabc,

title = "Reduced Susceptibility to Azoles in Cryptococcus gattii Correlates with the Substitution R258L in a Substrate Recognition Site of the Lanosterol 14-α-Demethylase",

abstract = "Cryptococcus neoformans and Cryptococcus gattii cause cryptococcosis, a lifethreatening fungal infection affecting mostly immunocompromised patients. In fact, cryptococcal meningitis accounts for about 19% of AIDS-related deaths in the world. Because of long-term azole therapies to treat this mycosis, resistance to fluconazole leading to treatment failure and poor prognosis has long been reported for both fungal species. Among the mechanisms implicated in resistance to azoles, mutations in the ERG11 gene, encoding the azole target enzyme lanosterol 14-a-demethylase, have been described. This study aimed to establish the amino acid composition of ERG11 of Colombian clinical isolates of C. neoformans and C. gattii and to correlate any possible substitution with the in vitro susceptibility profile of the isolates to fluconazole, voriconazole, and itraconazole. Antifungal susceptibility testing results showed that C. gattii isolates are less susceptible to azoles than C. neoformans isolates, which could correlate with differences in the amino acid composition and structure of ERG11 of each species. In addition, in a C. gattii isolate with high MICs for fluconazole (64 mg/mL) and voriconazole (1 mg/mL), a G973T mutation resulting in the substitution R258L, located in substrate recognition site 3 of ERG11, was identified. This finding suggests the association of the newly reported substitution with the azole resistance phenotype in C. gattii. Further investigations are needed to determine the exact role that R258L plays in the decreased susceptibility to fluconazole and voriconazole, as well as to determine the participation of additional mechanisms of resistance to azole drugs.",

author = "Carvajal, {Silvia Katherine} and Javier Melendres and Patricia Escand{\'o}n and Carolina Firacative",

note = "Funding Information: We thank the National Reference Laboratory of the National Institutes of Health for allowing the use of the strains. We also thank the public health laboratories in Colombia that take part in the National Surveillance Program of Cryptococcus and Cryptococcosis as well as the clinicians and epidemiologists of the participating hospitals. Carolina Firacative was supported by small grant no. IV-FPC014 from the Direcci{\'o}n de Investigaci{\'o}n e Innovaci{\'o}n, Universidad del Rosario. We report no conflicts of interest. Publisher Copyright: {\textcopyright} 2023 Carvajal et al.",

year = "2023",

month = aug,

day = "17",

doi = "10.1128/spectrum.01403-23",

language = "English (US)",

volume = "11",

pages = "1--11",

journal = "Microbiology spectrum",

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publisher = "American Society for Microbiology",

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Reduced Susceptibility to Azoles in Cryptococcus gattii Correlates with the Substitution R258L in a Substrate Recognition Site of the Lanosterol 14-α-Demethylase. / Carvajal, Silvia Katherine; Melendres, Javier; Escandón, Patricia et al.
En: Microbiology spectrum, Vol. 11, N.º 4, e0140323, 17.08.2023, p. 1-11.

Producción científica: Contribución a una revista › Artículo de Investigación › revisión exhaustiva

TY - JOUR

T1 - Reduced Susceptibility to Azoles in Cryptococcus gattii Correlates with the Substitution R258L in a Substrate Recognition Site of the Lanosterol 14-α-Demethylase

AU - Carvajal, Silvia Katherine

AU - Melendres, Javier

AU - Escandón, Patricia

AU - Firacative, Carolina

N1 - Funding Information: We thank the National Reference Laboratory of the National Institutes of Health for allowing the use of the strains. We also thank the public health laboratories in Colombia that take part in the National Surveillance Program of Cryptococcus and Cryptococcosis as well as the clinicians and epidemiologists of the participating hospitals. Carolina Firacative was supported by small grant no. IV-FPC014 from the Dirección de Investigación e Innovación, Universidad del Rosario. We report no conflicts of interest. Publisher Copyright: © 2023 Carvajal et al.

PY - 2023/8/17

Y1 - 2023/8/17

N2 - Cryptococcus neoformans and Cryptococcus gattii cause cryptococcosis, a lifethreatening fungal infection affecting mostly immunocompromised patients. In fact, cryptococcal meningitis accounts for about 19% of AIDS-related deaths in the world. Because of long-term azole therapies to treat this mycosis, resistance to fluconazole leading to treatment failure and poor prognosis has long been reported for both fungal species. Among the mechanisms implicated in resistance to azoles, mutations in the ERG11 gene, encoding the azole target enzyme lanosterol 14-a-demethylase, have been described. This study aimed to establish the amino acid composition of ERG11 of Colombian clinical isolates of C. neoformans and C. gattii and to correlate any possible substitution with the in vitro susceptibility profile of the isolates to fluconazole, voriconazole, and itraconazole. Antifungal susceptibility testing results showed that C. gattii isolates are less susceptible to azoles than C. neoformans isolates, which could correlate with differences in the amino acid composition and structure of ERG11 of each species. In addition, in a C. gattii isolate with high MICs for fluconazole (64 mg/mL) and voriconazole (1 mg/mL), a G973T mutation resulting in the substitution R258L, located in substrate recognition site 3 of ERG11, was identified. This finding suggests the association of the newly reported substitution with the azole resistance phenotype in C. gattii. Further investigations are needed to determine the exact role that R258L plays in the decreased susceptibility to fluconazole and voriconazole, as well as to determine the participation of additional mechanisms of resistance to azole drugs.

AB - Cryptococcus neoformans and Cryptococcus gattii cause cryptococcosis, a lifethreatening fungal infection affecting mostly immunocompromised patients. In fact, cryptococcal meningitis accounts for about 19% of AIDS-related deaths in the world. Because of long-term azole therapies to treat this mycosis, resistance to fluconazole leading to treatment failure and poor prognosis has long been reported for both fungal species. Among the mechanisms implicated in resistance to azoles, mutations in the ERG11 gene, encoding the azole target enzyme lanosterol 14-a-demethylase, have been described. This study aimed to establish the amino acid composition of ERG11 of Colombian clinical isolates of C. neoformans and C. gattii and to correlate any possible substitution with the in vitro susceptibility profile of the isolates to fluconazole, voriconazole, and itraconazole. Antifungal susceptibility testing results showed that C. gattii isolates are less susceptible to azoles than C. neoformans isolates, which could correlate with differences in the amino acid composition and structure of ERG11 of each species. In addition, in a C. gattii isolate with high MICs for fluconazole (64 mg/mL) and voriconazole (1 mg/mL), a G973T mutation resulting in the substitution R258L, located in substrate recognition site 3 of ERG11, was identified. This finding suggests the association of the newly reported substitution with the azole resistance phenotype in C. gattii. Further investigations are needed to determine the exact role that R258L plays in the decreased susceptibility to fluconazole and voriconazole, as well as to determine the participation of additional mechanisms of resistance to azole drugs.

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DO - 10.1128/spectrum.01403-23

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Reduced Susceptibility to Azoles in Cryptococcus gattii Correlates with the Substitution R258L in a Substrate Recognition Site of the Lanosterol 14-α-Demethylase

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