Abstract
Candida albicans, one of the most common fungal pathogens, is responsible for several yeast infections in human hosts, being resistant to classically used antifungal drugs, such as azole drugs. Multifactorial and multistep alterations are involved in the azole resistance in Candida albicans. In this study, a FCZ-resistant C. albicans strain was obtained by serial cultures of a FCZ-susceptible C. albicans strain in incrementally increasing concentrations of FCZ. We performed an integrated profile of different classes of molecules related to azole resistance in C. albicans by combining several mass-spectrometry based methodologies. The comparative metabolomic study was performed with the sensitive and resistant strains of C.albicans to identify metabolites altered during the development of resistance to fluconazole, while the intervention strains and non-intervention strains of C.albicans to identify metabolites altered involved in cross-resistant to azole drugs. Our analysis of the different metabolites identified molecules mainly involved in metabolic processes such as amino acid metabolism, tricarboxylic acid cycle and phospholipid metabolism. We also compared the phospholipid composition of each group, revealing that the relative content of phospholipids significantly changed during the development of resistance to azole drugs. According with these results, we hypothesized that the metabolism shift might contribute to azole drugs resistance in C.albicans from multifactorial alterations. Our result paves the way to understand processes underlying the resistance to azole drugs in C. albicans, providing the basis for developing new antifungal drugs.
Highlights
Candida albicans is an asexual opportunistic fungus that causes infections in immunocompromised and debilitated individuals[1]
Reduced sensitivity to FCZ was detected after 5 passages, the high-level resistant strain (FCZ minimal inhibitory concentration (MIC) = 256 μg/mL) was generated after about 51 passages and the generations were cultivated in YPD medium with fluconazole (MIC = 512 μg/mL) and retained the resistant phenotype for more than 15 passages (Fig 1)
Different MS-based approaches were used to investigate the metabolic profile associated with azole resistance in C. albicans
Summary
Candida albicans is an asexual opportunistic fungus that causes infections in immunocompromised and debilitated individuals[1]. Azole drugs are widely used in clinical practice having a good antibacterial power and low side effects[2]. Identification of potential biomarkers associate with azole resistance in Candida albicans to high-concentration use of drugs and prolonged therapies. A strong mobilization of the scientific community allowed elucidation of the molecular mechanisms underlying fluconazole resistance in the yeasts Candida, of which a number of them could be extrapolated to other azole drugs, such as mutations in the ERG11 gene, overexpression of efflux membrane transporters and overexpression of ERG11[4]. Almost all metabolomics approaches can be classified as targeted or untargeted. Due to the wide range of metabolite concentrations and the diversity of their biochemical properties, no single analytical technique can provide a fully characterization of the metabolic profile of an organism. High-performance liquid chromatography mass spectrometry (HPLC-MS) and gas chromatography MS (GC-MS) are two widely used techniques for metabolomics analysis
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