Narrow mutational signatures drive acquisition of multidrug resistance in the fungal pathogen Candida glabrata.
Narrow mutational signatures drive acquisition of multidrug resistance in the fungal pathogen Candida glabrata.
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DOI：
10.1016/j.cub.2021.09.084
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发表时间：
2021-12-06
期刊：
影响因子：
--
通讯作者：
Gabaldón T
中科院分区：
文献类型：
--
作者：
Ksiezopolska E;Schikora-Tamarit MÀ;Beyer R;Nunez-Rodriguez JC;Schüller C;Gabaldón T
真菌感染是一个日益严重的医学问题，部分原因是对一种或多种抗真菌药物的耐药性增加。然而，支持获得抗真菌耐药性的进化过程却知之甚少。在这里，我们用实验微进化的方法研究了酵母菌光滑假丝酵母菌对氟康唑和阿尼达芬净这两种广泛使用的不同作用机制的抗真菌药物的适应性。我们的结果表明，人们普遍具有对一种或两种药物快速适应的能力。耐药性，包括多药耐药性，通常是以适中的适应成本获得的，并由有限的一组基因突变介导，这些基因在适应每种药物的菌株中反复发生特定突变。重要的是，我们发现ERG3突变在对阿尼达芬净耐药和对氟康唑交叉耐药中的双重作用在阿尼达芬净耐药菌株子集中。我们的结果揭示了导致抗真菌药物耐药和交叉耐药的突变途径。快速获得耐药性的能力在光滑假丝酵母菌中广泛存在，导致耐药性的突变非常多样，但只影响一小部分基因，对氟康唑的交叉耐药在适应阿尼杜拉芬净的菌株中很常见，ERG3突变经常导致阿尼杜拉芬净耐药菌株Ksiezopolska等人对氟康唑产生耐药性。在真菌病原菌光滑念珠菌中追踪导致耐药性的突变路径，并发现新的耐药性相关基因。重要的是，他们发现ERG3基因的突变支持了只对阿尼度芬净耐药的菌株对氟康唑交叉耐药的常见现象。
Fungal infections are a growing medical concern, in part due to increased resistance to one or multiple antifungal drugs. However, the evolutionary processes underpinning the acquisition of antifungal drug resistance are poorly understood. Here, we used experimental microevolution to study the adaptation of the yeast pathogen Candida glabrata to fluconazole and anidulafungin, two widely used antifungal drugs with different modes of action. Our results show widespread ability of rapid adaptation to one or both drugs. Resistance, including multidrug resistance, is often acquired at moderate fitness costs and mediated by mutations in a limited set of genes that are recurrently and specifically mutated in strains adapted to each of the drugs. Importantly, we uncover a dual role of ERG3 mutations in resistance to anidulafungin and cross-resistance to fluconazole in a subset of anidulafungin-adapted strains. Our results shed light on the mutational paths leading to resistance and cross-resistance to antifungal drugs. The ability for fast acquisition of drug resistance is widespread in Candida glabrata Resistance-conferring mutations are very diverse but affect a small number of genes Cross-resistance to fluconazole is common in strains adapted to anidulafungin ERG3 mutations often drive fluconazole resistance in anidulafungin-adapted strains Ksiezopolska et al. trace mutational paths leading to drug resistance in the fungal pathogen Candida glabrata and uncover new resistance-related genes. Importantly, they find that mutations in the ERG3 gene underpin the common appearance of cross-resistance to fluconazole in strains adapted only to anidulafungin.
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影响因子：
3.2
作者：
Gabaldón T;Carreté L
通讯作者：
Carreté L
DOI：
10.3390/antibiotics9120877
发表时间：
2020-12-08
期刊：
Antibiotics (Basel, Switzerland)
影响因子：
--
作者：
Arastehfar A;Gabaldón T;Garcia-Rubio R;Jenks JD;Hoenigl M;Salzer HJF;Ilkit M;Lass-Flörl C;Perlin DS
通讯作者：
Perlin DS
影响因子：
11.3
作者：
Consortium OPATHY;Gabaldón T
通讯作者：
Gabaldón T
机会性病原体念珠菌中基因组变异的模式表明，交配的存在和与人类的二次关联。
DOI：
10.1016/j.cub.2017.11.027
发表时间：
2018-01-08
期刊：
Current biology : CB
影响因子：
--
作者：
Carreté L;Ksiezopolska E;Pegueroles C;Gómez-Molero E;Saus E;Iraola-Guzmán S;Loska D;Bader O;Fairhead C;Gabaldón T
通讯作者：
Gabaldón T
影响因子：
4.9
作者：
Cavalheiro M;Costa C;Silva-Dias A;Miranda IM;Wang C;Pais P;Pinto SN;Mil-Homens D;Sato-Okamoto M;Takahashi-Nakaguchi A;Silva RM;Mira NP;Fialho AM;Chibana H;Rodrigues AG;Butler G;Teixeira MC
通讯作者：
Teixeira MC