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Bis(methyl)gliotoxin and gliotoxin in bronchoalveolar lavage fluids are not suitable markers for invasive aspergillosis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Introduction: Invasive aspergillosis is challenging to diagnose partly due to shortcomings in sensitivity, reliability, and selectivity of current diagnostic methods, which rely on cultures, assays, and histopathology. This problem may be addressed by chemical analysis of metabolites in lung fluid from infected patients. Gliotoxin and bis(methyl)gliotoxin have been pinpointed as potential marker metabolites in serum and plasma for invasive aspergillosis patients, but whether lung fluid samples could be assessed for these markers is still unknown.

Methods: Bronchoalveolar lavage samples were taken from 42 individuals with a variety of pulmonary diseases whereof  20 were diagnosed with possible invasive aspergillosis. The samples were analyzed with ultra high performance liquid chromatography coupled to triple quadropole time-of-flight mass spectrometry to investigate the use of the Aspergillus fumigatus metabolites gliotoxin and bis(methyl)gliotoxin as marker metabolites for invasive aspergillosis.

Results: Gliotoxin was not detected in any of the 42 samples, but  bis(methyl)gliotoxin in 10 (24%). Bis(methyl)gliotoxin was detected in 5 (25%) of the 20 patients with possible IA and in 5 (23%) in the other 22 samples. One unknown compound (357.30 m/z) with a similar mass spectrum profile to bis(methyl)gliotoxin (357.09 m/z) was found in 32 (76%) of all samples.

Conclusions: Neither gliotoxin nor bis(methyl)gliotoxin appears to be an acceptable marker metabolite in bronchoalveolar lavage fluids for invasive aspergillosis. Further development of MS-based analyses should include chromatography. 

Keyword [en]
Invasive aspergillosis, gliotoxin, bis(methyl)gliotoxin, Aspergillus fumigatus, diagnosis
National Category
Medicinal Chemistry
Research subject
Pharmacognosy
Identifiers
URN: urn:nbn:se:uu:diva-242610OAI: oai:DiVA.org:uu-242610DiVA: diva2:784271
Available from: 2015-01-28 Created: 2015-01-28 Last updated: 2015-03-11Bibliographically approved
In thesis
1. Analysis of Secondary Metabolites from Aspergillus fumigatus and Penicillium nalgiovense: Antimicrobial Compounds from Filamentous Fungi Isolated from Extreme Environments
Open this publication in new window or tab >>Analysis of Secondary Metabolites from Aspergillus fumigatus and Penicillium nalgiovense: Antimicrobial Compounds from Filamentous Fungi Isolated from Extreme Environments
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes the cultivation and extraction of filamentous fungi isolated from extreme environments in the search for new antibiotic compounds. Filamentous fungi are a rich source of medicines including antibiotics, and it is believed that many currently unknown fungal species and bioactive fungal metabolites remain to be discovered.

Aspergillus fumigatus and Penicillium nalgiovense strains were isolated from an antibiotic-contaminated riverbed near Hyderabad, India, and soil taken from a penguin’s nest on Paulete Island, Antarctica, respectively. It was anticipated that the extreme conditions within these environments would exert unusual selective pressures on their filamentous fungi, possibly causing the secretion of new bioactive compounds.

The cultivation, extraction and analysis of metabolites from the A. fumigatus strain resulted in the isolation of the antimicrobial substance gliotoxin. Subsequent investigations revealed that this strain’s secretion of gliotoxin was increased by as much as 65 % when it was cultivated in the presence of pathogen-associated molecular patterns. These results indicate the existence of a fungal receptor/signaling system for detecting nearby bacteria. The scope for using gliotoxin and the related metabolite bis(methyl)gliotoxin as biomarker metabolites for diagnosing the lethal pulmonary condition invasive aspergillosis was also investigated. Bronchoalveolar lavage fluid from 42 patients with and without possible invasive aspergillosis was extracted and analyzed. The results obtained suggest that gliotoxin and bis(methyl)gliotoxin are not suitable markers for diagnosing invasive aspergillosis.

Studies on the P. nalgiovense strain from Antarctica resulted in the isolation of the antifungal agent amphotericin B. The secretion of this compound increased when P. nalgiovense was cultured on a potato-dextrose agar enriched with coconut flakes rather than liquid RPMI 1640 medium. This was the first time amphotericin B was isolated from any organism other than the bacterium Streptomyces nodosus.

The results presented in this thesis will be useful in the continuing search for novel bioactive compounds, the diagnosis of fungal infections, and as a source of insight into the interactions between microorganisms. Moreover, they show that even extensively studied fungal genera such as Aspergillus and Penicillium are not completely understood and may produce unexpected or previously unknown bioactive metabolites under appropriate conditions.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 195
Keyword
Aspergillus fumigatus, Penicillium nalgiovense, secondary metabolites, invasive aspergillosis, elicitation, gliotoxin, bis(methyl)gliotoxin, amphotericin B
National Category
Medicinal Chemistry
Research subject
Pharmacognosy
Identifiers
urn:nbn:se:uu:diva-242611 (URN)978-91-554-9154-3 (ISBN)
Public defence
2015-03-20, BMC sal B22, Husargatan 4, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2015-02-25 Created: 2015-01-28 Last updated: 2015-03-11

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Svahn, StefanGöransson, UlfBohlin, LarsJanson, ChristerOlsen, Björn

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