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Antimicrobial drug resistance poses a global health threat, requiring a deeper understanding of the evolutionary processes that lead to its emergence in pathogens. Complex evolutionary dynamics involve multiple mutations that can result in cooperative or competitive (clonal interference) effects. Candida albicans, a major fungal pathogen, displays high rates of copy number variation (CNV) and loss of heterozygosity (LOH). CNV and LOH events involve large numbers of genes and could synergize during evolutionary adaptation. Understanding the contributions of CNV and LOH to antifungal drug adaptation is challenging, especially in the context of whole-population genome sequencing. Here, we document the sequential evolution of fluconazole tolerance and then resistance in a C. albicans isolate involving an initial CNV on chromosome 4, followed by an LOH on chromosome R that involves KSR1. Similar LOH events involving KSR1, which encodes a reductase in the sphingolipid biosynthesis pathway, were also detected in independently evolved fluconazole resistant isolates. We dissect the specific KSR1 codons that affect fluconazole resistance and tolerance. The combination of the chromosome 4 CNV and KSR1 LOH results in a >500-fold decrease in azole susceptibility relative to the progenitor, illustrating a compelling example of rapid, yet step-wise, interplay between CNV and LOH in drug resistance evolution. Author summary: The rise of drug-resistant microbes is a global health crisis. To combat this, we need to understand how these organisms evolve drug resistance. This study focuses on Candida albicans, a common fungal pathogen, and its ability to develop resistance to fluconazole, a widely used antifungal drug. We observe C. albicans rapidly evolve drug resistance through a two-step process involving large-scale genetic changes. First, it undergoes a copy number amplification, then it undergoes a loss of heterozygosity at the KSR1 gene, which is involved in sphingolipid biosynthesis. These changes work together to dramatically increase the fungus's ability to survive in the presence of the drug. This research highlights how quickly and efficiently yeast can adapt to overcome antifungal drug and emphasizes the importance of studying large-scale genetic changes, not just individual mutations, when investigating drug resistance. Our findings could help in developing new strategies to predict and prevent the emergence of resistant pathogens, ultimately improving patient care in the face of this growing threat. [ABSTRACT FROM AUTHOR]

Invasive fungal diseases are increasing issues in modern medicine, where the human immunodeficiency virus (HIV) pandemic and the wider use of immunosuppressive drugs generate an ever-growing number of immunocompromised patients with an increased susceptibility to uncommon fungal pathogens. In the past decade, new species have been reported as being responsible for disseminated and invasive fungal diseases in humans. Among them, the following genera are rare but seem emerging issues: Scopulariopsis, Hormographiella, Emergomyces, Westerdykella, Trametes, Actinomucor, Saksenaea, Apophysomyces , and Rhytidhysteron. Delay in diagnosis, which is often the case in these infections, jeopardizes patients' prognosis and leads to increased mortality. Here we summarize the clinical and biological presentation and the key features to identify these emerging pathogens and we discuss the available antifungal classes to treat them. We focused on Pubmed to recover extensively reported human invasive cases and articles regarding the nine previously cited fungal organisms. Information concerning patient background, macroscopic and microscopic description and pictures of these fungal organisms, histological features in tissues, findings with commonly used antigen tests in practice, and hints on potential efficient antifungal classes were gathered. This review's purpose is to help clinical microbiologists and physicians to suspect, identify, diagnose, and treat newly encountered fungi in hospital settings. [ABSTRACT FROM AUTHOR]