Aspergillus fumigatus Can Display Persistence to the Fungicidal Drug Voriconazole.

Autor:	Scott J; Manchester Fungal Infection Group, Division of Evolution, Infection, and Genomics, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom., Valero C; Manchester Fungal Infection Group, Division of Evolution, Infection, and Genomics, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.; Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil., Mato-López Á; Mycology Reference Laboratory (Laboratorio de Referencia e Investigación en Micología [LRIM]), National Centre for Microbiology, Instituto de Salud Carlos III (ISCIII), Majadahonda, Madrid, Spain., Donaldson IJ; Bioinformatics Core Facility, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom., Roldán A; Mycology Reference Laboratory (Laboratorio de Referencia e Investigación en Micología [LRIM]), National Centre for Microbiology, Instituto de Salud Carlos III (ISCIII), Majadahonda, Madrid, Spain., Chown H; Manchester Fungal Infection Group, Division of Evolution, Infection, and Genomics, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom., Van Rhijn N; Manchester Fungal Infection Group, Division of Evolution, Infection, and Genomics, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom., Lobo-Vega R; Mycology Reference Laboratory (Laboratorio de Referencia e Investigación en Micología [LRIM]), National Centre for Microbiology, Instituto de Salud Carlos III (ISCIII), Majadahonda, Madrid, Spain., Gago S; Manchester Fungal Infection Group, Division of Evolution, Infection, and Genomics, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom., Furukawa T; Manchester Fungal Infection Group, Division of Evolution, Infection, and Genomics, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom., Morogovsky A; Department of Clinical Microbiology and Immunology, Sackler School of Medicine Ramat-Aviv, Tel-Aviv, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Ben Ami R; Department of Clinical Microbiology and Immunology, Sackler School of Medicine Ramat-Aviv, Tel-Aviv, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Bowyer P; Manchester Fungal Infection Group, Division of Evolution, Infection, and Genomics, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom., Osherov N; Department of Clinical Microbiology and Immunology, Sackler School of Medicine Ramat-Aviv, Tel-Aviv, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Fontaine T; Institut Pasteur, Université de Paris, INRAE, USC2019, Unité Biologie et Pathogénicité Fongiques, Paris, France., Goldman GH; Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil., Mellado E; Mycology Reference Laboratory (Laboratorio de Referencia e Investigación en Micología [LRIM]), National Centre for Microbiology, Instituto de Salud Carlos III (ISCIII), Majadahonda, Madrid, Spain.; CiberInfec ISCIII, CIBER en Enfermedades Infecciosas, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain., Bromley M; Manchester Fungal Infection Group, Division of Evolution, Infection, and Genomics, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom., Amich J; Manchester Fungal Infection Group, Division of Evolution, Infection, and Genomics, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.; Mycology Reference Laboratory (Laboratorio de Referencia e Investigación en Micología [LRIM]), National Centre for Microbiology, Instituto de Salud Carlos III (ISCIII), Majadahonda, Madrid, Spain.
Jazyk:	angličtina
Zdroj:	Microbiology spectrum [Microbiol Spectr] 2023 Mar 13, pp. e0477022. Date of Electronic Publication: 2023 Mar 13.
DOI:	10.1128/spectrum.04770-22
Abstrakt:	Aspergillus fumigatus is a filamentous fungus that can infect the lungs of patients with immunosuppression and/or underlying lung diseases. The mortality associated with chronic and invasive aspergillosis infections remain very high, despite availability of antifungal treatments. In the last decade, there has been a worrisome emergence and spread of resistance to the first-line antifungals, the azoles. The mortality caused by resistant isolates is even higher, and patient management is complicated as the therapeutic options are reduced. Nevertheless, treatment failure is also common in patients infected with azole-susceptible isolates, which can be due to several non-mutually exclusive reasons, such as poor drug absorption. In addition, the phenomena of tolerance or persistence, where susceptible pathogens can survive the action of an antimicrobial for extended periods, have been associated with treatment failure in bacterial infections, and their occurrence in fungal infections already proposed. Here, we demonstrate that some isolates of A. fumigatus display persistence to voriconazole. A subpopulation of the persister isolates can survive for extended periods and even grow at low rates in the presence of supra-MIC of voriconazole and seemingly other azoles. Persistence cannot be eradicated with adjuvant drugs or antifungal combinations and seemed to reduce the efficacy of treatment for certain individuals in a Galleria mellonella model of infection. Furthermore, persistence implies a distinct transcriptional profile, demonstrating that it is an active response. We propose that azole persistence might be a relevant and underestimated factor that could influence the outcome of infection in human aspergillosis. IMPORTANCE The phenomena of antibacterial tolerance and persistence, where pathogenic microbes can survive for extended periods in the presence of cidal drug concentrations, have received significant attention in the last decade. Several mechanisms of action have been elucidated, and their relevance for treatment failure in bacterial infections demonstrated. In contrast, our knowledge of antifungal tolerance and, in particular, persistence is still very limited. In this study, we have characterized the response of the prominent fungal pathogen Aspergillus fumigatus to the first-line therapy antifungal voriconazole. We comprehensively show that some isolates display persistence to this fungicidal antifungal and propose various potential mechanisms of action. In addition, using an alternative model of infection, we provide initial evidence to suggest that persistence may cause treatment failure in some individuals. Therefore, we propose that azole persistence is an important factor to consider and further investigate in A. fumigatus.
Databáze:	MEDLINE
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