The early transcriptional and post-transcriptional responses to fluconazole in sensitive and resistant Candida albicans

• Published in: Scientific reports 2024-11, Vol.14 (1), p.29012-10, Article 29012
• Main Authors: Stevens, Irene, Silao, Fitz Gerald, Huch, Susanne, Liu, Honglian, Ryman, Kicki, Carvajal-Jimenez, Adriana, Ljungdahl, Per O., Pelechano, Vicent
• Format: Article
• Language: English
• Subjects: 631/1647/514/1949; 631/326/193/2541; 631/326/421; 631/337/1645/2020; 631/337/2019; Amino acids; Antifungal agents; Antifungal Agents - pharmacology; Candida albicans; Candida albicans - drug effects; Candida albicans - genetics; Candidemia; Drug Resistance, Fungal - genetics; Exonuclease; Fluconazole; Fluconazole - pharmacology; Gene Expression Regulation, Fungal - drug effects; Humanities and Social Sciences; Humans; Immunocompromised hosts; Intermediates; Microbial Sensitivity Tests; mRNA turnover; multidisciplinary; Post-transcription; Ribonucleic acid; Ribosomes - drug effects; Ribosomes - metabolism; RNA; RNA Stability - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Transcription, Genetic - drug effects
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-80435-w

Candida albicans is a leading cause of fungal infections in immunocompromised patients. Management of candidemia relies on a few antifungal agents, with fluconazole being first line therapy. The emergence of fluconazole-resistant strains highlights the pressing need to improve our molecular understanding of the drug response mechanisms. By sequencing the 5’P mRNA degradation intermediates, we establish that co-translational mRNA decay occurs in C. albicans and characterize how in vivo 5´-3´ exonuclease degradation trails the last translating ribosome. Thus, the study of the 5’ Phosphorylated mRNA degradome (5PSeq) offers a simple and affordable way to measure ribosome dynamics and identify codon specific ribosome stalls in response to drugs and amino acid deprivation. Building upon this, we combine RNA-Seq and 5PSeq to study the early response of sensitive and resistant C. albicans isolates to fluconazole. Our results highlight that transcriptional responses, rather than changes in ribosome dynamics, are the main driver of Candida resistance to fluconazole.