Fig. 1: Changes in gene copy number can lead to resistance through 4 main mechanisms.
From: The role of gene copy number variation in antimicrobial resistance in human fungal pathogens
a Illustration of four mechanisms through which CNVs can lead to antifungal resistance. i) CNVs leading to overexpression of a drug target protein can confer resistance. In cases where drug concentration is low, a high enough concentration of the drug target can lead to enough copies of the protein that are free of drug binding to allow cell survival. ii) CNV-mediated overexpression of small molecule efflux pumps could confer resistance to certain antifungal drugs. Different pumps can significantly reduce the intracellular concentration of certain molecules, including certain antifungal drugs. iii) Changes to cell metabolism brought on by CNVs can confer resistance. Changes in the copy number of metabolic enzymes (light purple) can modify the metabolic flux in the cell and lead to resistance in various pathways. In particular, CNVs affecting enzymes involved in cell membrane and cell wall synthesis can change the composition of these structures, and thus modulate the effect of antifungal drugs. iv) Stress response mechanisms and proteins, including chaperones, play an important role in the antifungal drug response101,102,103,104, and so CNVs that affect the activity of stress response pathways could have a large impact on fungi’s ability to adapt to antifungal drugs. b Count of the mechanisms through which CNVs confer antifungal resistance. The bar plot indicates the number of reported examples of each mechanism in the literature (as described in panel a), for each species.“Other” indicates proposed mechanisms that do not neatly fit into one of the categories, and “Unknown” indicates that no potential mechanism was reported. The pie chart titled “Strain origin” indicates whether the CNV was found in a clinical, a laboratory, or an environmental strain. The pie chart titled “Clinical only” represents the mechanisms of resistance found for only the strains of clinical origin. All data used in making panel b are available in Supplementary Table 1.
