Challenging the Paradigm of Clinical Triazole Resistance in Aspergillus fumigatus
type: CreativeWork
description: Invasive aspergillosis is a leading cause of morbidity and mortality among immunocompromised populations and is predicted to cause more than 200,000 life- threatening infections each year. Aspergillus fumigatus is the most prevalent pathogen isolated from patients with invasive aspergillosis, accounting for more than 60% of all cases. Currently, the only antifungal agents available with consistent activity against A. fumigatus are the mold-active triazoles and amphotericin B, of which the triazoles commonly represent both front-line and salvage therapeutic options. Unfortunately, the treatment of infections caused by A. fumigatus has recently been further complicated by the global emergence of triazole resistance among both clinical and environmental isolates, and a large proportion of this resistance remains unexplained. In this work, we characterize the contributions of previously identified mechanisms of triazole resistance, including mutations in the sterol-demethylase- encoding gene cyp51A, overexpression of sterol-demethylase genes, and overexpression of the efflux pump-encoding gene abcC, among a large collection of highly triazole- resistant clinical A. fumigatus isolates. Upon revealing that these mechanisms alone cannot substantiate the majority of triazole resistance exhibited by this collection, we then characterize the direct contribution of two additional efflux pump-encoding genes, abcA and atrI. Increased expression of abcA and atrI has previously been associated with triazole resistance in clinical isolates of A. fumigatus, and both of these genes exhibit a high degree of homology with the well characterized Candida albicans triazole efflux pump-encoding gene, CDR1. However, deletion of either abcA or atrI in triazole-resistant clinical isolates which overexpress these genes, did not result in a significant change in triazole susceptibility. Finally, upon demonstrating that the canonical mechanisms of triazole resistance poorly explain the high leve…
abstract: Invasive aspergillosis is a leading cause of morbidity and mortality among immunocompromised populations and is predicted to cause more than 200,000 life- threatening infections each year. Aspergillus fumigatus is the most prevalent pathogen isolated from patients with invasive aspergillosis, accounting for more than 60% of all cases. Currently, the only antifungal agents available with consistent activity against A. fumigatus are the mold-active triazoles and amphotericin B, of which the triazoles commonly represent both front-line and salvage therapeutic options. Unfortunately, the treatment of infections caused by A. fumigatus has recently been further complicated by the global emergence of triazole resistance among both clinical and environmental isolates, and a large proportion of this resistance remains unexplained. In this work, we characterize the contributions of previously identified mechanisms of triazole resistance, including mutations in the sterol-demethylase- encoding gene cyp51A, overexpression of sterol-demethylase genes, and overexpression of the efflux pump-encoding gene abcC, among a large collection of highly triazole- resistant clinical A. fumigatus isolates. Upon revealing that these mechanisms alone cannot substantiate the majority of triazole resistance exhibited by this collection, we then characterize the direct contribution of two additional efflux pump-encoding genes, abcA and atrI. Increased expression of abcA and atrI has previously been associated with triazole resistance in clinical isolates of A. fumigatus, and both of these genes exhibit a high degree of homology with the well characterized Candida albicans triazole efflux pump-encoding gene, CDR1. However, deletion of either abcA or atrI in triazole-resistant clinical isolates which overexpress these genes, did not result in a significant change in triazole susceptibility. Finally, upon demonstrating that the canonical mechanisms of triazole resistance poorly explain the high leve…
author: Rybak, Jeffrey Michael
keywords: Aspergillus, resistance, triazole, Medicine and Health Sciences, Microbiology
date published: 2019-05-01T07:00:00Z
date modified: 2026-07-24T05:00:33Z
provider: University of Tennessee Health Science Center
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Tennessee Health Science Center