Acquired resistance or tolerance? – in search of mechanisms underlying changes in the resistance profile of Candida albicans and Candida parapsilosis as a result of exposure to methotrexate

IF 2.2 4区医学 Q3 MYCOLOGY Journal de mycologie medicale Pub Date : 2024-03-15 DOI:10.1016/j.mycmed.2024.101476

Katarzyna Góralska , Małgorzata Szybka , Filip Franciszek Karuga , Dorota Pastuszak-Lewandoska , Ewa Brzeziańska-Lasota

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Abstract

The increasing prevalence of fungal strains showing acquired resistance and multidrug resistance is an increasing therapeutic problem, especially in patients with a severely weakened immune system and undergoing chemotherapy. What is also extremely disturbing is the similarity of the resistance mechanisms of fungal cells and other eukaryotic cells, including human cells, which may contribute to the development of cross-resistance in fungi in response to substances used in e.g. anticancer treatment. An example of such a drug is methotrexate, which is pumped out of eukaryotic cells by ABC transmembrane transporters - in fungi, used to remove azoles from fungal cells.

For this reason, the aim of the study was to analyze the expression levels of genes: ERG11, MDR1 and CDR1, potentially responsible for the occurrence of cross-resistance in Candida albicans and Candida parapsilosis as a result of fungal exposure to methotrexate (MTX).

In vitro exposure of C. albicans and C. parapsilosis strains to methotrexate showed a high increase in resistance to fluconazole and a partial increase in resistance to voriconazole. Analysis of the expression of resistance genes showed varied responses of the tested strains depending on the species. In the case of C. albicans, an increase in the expression of the MDR1 gene was observed, and a decrease in ERG11 and CDR1. However, for C. parapsilosis there was an increase in the expression of the CDR1 gene and a decrease in ERG11 and MDR1.

We noted the relationship between the level of resistance to voriconazole and the level of ERG11 gene expression in C. albicans. This indicates that this type of relationship is different for each species. Our research confirms that the mechanisms by which fungi acquire resistance and develop cross-resistance are highly complex and most likely involve several pathways simultaneously. The emergence of multidrug resistance may be related to the possibility of developing tolerance to antimycotics by fungi.

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获得性抗药性还是耐受性？- 寻找暴露于甲氨蝶呤后白色念珠菌和副丝状念珠菌耐药性特征变化的机制

越来越多的真菌菌株表现出获得性抗药性和多药抗药性，这是一个日益严重的治疗问题，尤其是在免疫系统严重衰弱和正在接受化疗的病人身上。同样令人极为不安的是，真菌细胞和其他真核细胞（包括人体细胞）的抗药性机制相似，这可能导致真菌对抗癌治疗等药物产生交叉抗药性。甲氨蝶呤就是这样一种药物，它通过 ABC 跨膜转运体从真核细胞中排出，而在真菌中，ABC 跨膜转运体用于从真菌细胞中清除唑类药物：白念珠菌和副丝状念珠菌菌株体外接触甲氨蝶呤（MTX）后，发现它们对氟康唑的耐药性和对伏立康唑的部分耐药性都有所增强。对抗性基因表达的分析表明，受试菌株的反应因种类而异。白僵菌的 MDR1 基因表达增加，ERG11 和 CDR1 基因表达减少。我们注意到白僵菌对伏立康唑的耐药性水平与 ERG11 基因的表达水平之间存在关系。这表明这种关系对于每个物种都是不同的。我们的研究证实，真菌获得抗药性和产生交叉抗药性的机制非常复杂，很可能同时涉及多种途径。多药耐药性的出现可能与真菌对抗霉素产生耐受性有关。

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来源期刊

Journal de mycologie medicale 医学-真菌学

CiteScore

5.10

自引率

2.80%

发文量

审稿时长

6-12 weeks

期刊介绍： The Journal de Mycologie Medicale / Journal of Medical Mycology (JMM) publishes in English works dealing with human and animal mycology. The subjects treated are focused in particular on clinical, diagnostic, epidemiological, immunological, medical, pathological, preventive or therapeutic aspects of mycoses. Also covered are basic aspects linked primarily with morphology (electronic and photonic microscopy), physiology, biochemistry, cellular and molecular biology, immunochemistry, genetics, taxonomy or phylogeny of pathogenic or opportunistic fungi and actinomycetes in humans or animals. Studies of natural products showing inhibitory activity against pathogenic fungi cannot be considered without chemical characterization and identification of the compounds responsible for the inhibitory activity. JMM publishes (guest) editorials, original articles, reviews (and minireviews), case reports, technical notes, letters to the editor and information. Only clinical cases with real originality (new species, new clinical present action, new geographical localization, etc.), and fully documented (identification methods, results, etc.), will be considered. Under no circumstances does the journal guarantee publication before the editorial board makes its final decision. The journal is indexed in the main international databases and is accessible worldwide through the ScienceDirect and ClinicalKey platforms.