Aspergillus fumigatus is the most common cause of invasive fungal mold infections in immunocompromised individuals. Current antifungal treatment relies heavily on the triazole antifungals which inhibit fungal Erg11/Cyp51 activity and subsequent ergosterol biosynthesis. However, resistance, due primarily to cyp51 mutation, is rapidly increasing. A. fumigatus contains two Cyp51 isoenzymes, Cyp51A and Cyp51B. Overexpression and mutation of Cyp51A is a major cause of triazole resistance in A. fumigatus . The role of Cyp51B in generating resistance is unclear. Here we show that overexpression or mutation of cyp51B results in triazole resistance. We demonstrate that introduction of a G457S Cyp51B mutation identified in a resistant clinical isolate, results in voriconazole resistance in the naïve recipient strain. Our results indicate that mutations in cyp51B resulting in clinical resistance do exist and should be monitored.
Aspergillus fumigatus is the leading cause of life-threatening invasive mold infections in immunocompromised individuals. This ubiquitous saprophyte possesses several natural attributes allowing it to evade the immune system, including the ability to withstand high toxic Cu concentrations within the phagosomes of macrophages and neutrophils. We previously established that at high levels, Cu binds and activates the A. fumigatus transcription factor AceA, which upregulates the expression of the Cu exporter CrpA to expel excess Cu. Deletion of aceA or crpA result in extreme Cu sensitivity and attenuated virulence. To identify other elements participating in resistance to Cu, we performed a genome-wide analysis of the transcriptome by RNAseq to analyze the AceA-dependent response of A. fumigatus to excess Cu. We deleted key genes whose transcription was strongly upregulated by high Cu, including those encoding homologs of the three Cu chaperones cox17, atx1 and ccs1 . Detailed analysis of these genes indicates that in A. fumigatus, cox17 is an essential gene with a possible role in respiration, the atxA gene product participates in reductive iron uptake and ccsA encodes the Cu chaperone activating A. fumigatus Sod1. Interestingly, although the ccsA -null strain was extremely sensitive to high Cu and oxidative stress, it was not attenuated in virulence in a mouse model of invasive pulmonary aspergillosis. Our work provides (i) a detailed view of the genome-wide transcriptional response of A. fumigatus to excess Cu, (ii) identification of the AceA-dependent transcriptome and (iii) analysis of the roles of the three Cu chaperones cox17, atxA and ccsA.
It is well known that bacteria can transfer antibiotic resistance from one strain to another by horizontal gene transfer (HGT), leading to the current worldwide crisis of rapidly emerging antibiotic-resistant bacteria. However, in fungi, HGT events have only been indirectly documented by whole-genome sequencing.
Invasive aspergillosis (IA), caused predominantly by Aspergillus fumigatus , is the most common opportunistic mold infection in immunocompromised patients. Resistance of A. fumigatus to triazoles has been increasingly reported, leading to poor outcomes of IA to the front-line azoles.
The leading fungal pathogens causing systemic infections in humans are Candida spp., Aspergillus fumigatus, and Cryptococcus neoformans. The major class of antifungals used to treat such infections are the triazoles, which target the cytochrome P450 lanosterol 14-α-demethylase, encoded by the ERG11 (yeasts)/cyp51A (molds) genes, catalyzing a key step in the ergosterol biosynthetic pathway. Triazole resistance in clinical fungi is a rising concern worldwide, causing increasing mortality in immunocompromised patients. This review describes the use of serial clinical isolates and in-vitro evolution toward understanding the mechanisms of triazole resistance. We outline, compare, and discuss how these approaches have helped identify the evolutionary pathways taken by pathogenic fungi to acquire triazole resistance. While they all share a core mechanism (mutation and overexpression of ERG11/cyp51A and efflux transporters), their timing and mechanism differs: Candida and Cryptococcus spp. exhibit resistance-conferring aneuploidies and copy number variants not seen in A. fumigatus. Candida spp. have a proclivity to develop resistance by undergoing mutations in transcription factors (TAC1, MRR1, PDR5) that increase the expression of efflux transporters. A. fumigatus is especially prone to accumulate resistance mutations in cyp51A early during the evolution of resistance. Recently, examination of serial clinical isolates and experimental lab-evolved triazole-resistant strains using modern omics and gene editing tools has begun to realize the full potential of these approaches. As a result, triazole-resistance mechanisms can now be analyzed at increasingly finer resolutions. This newfound knowledge will be instrumental in formulating new molecular approaches to fight the rapidly emerging epidemic of antifungal resistant fungi.
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