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Preclinical Evaluation of Recombinant Microbial Glycoside Hydrolases in the Prevention of Experimental Invasive Aspergillosis

Ostapska, Hanna ; Raju, Deepa ; Lehoux, Melanie ; Lacdao, Ira ; Gilbert, Stephanie ; Sivarajah, Piyanka ; Bamford, Natalie C ; Baker, Perrin ; Nguyen, Thi Tuyet Mai ; Zacharias, Caitlin A ; Gravelat, Fabrice N ; Howell, P Lynne ; Sheppard, Donald C Chowdhary, Anuradha

mBio, 2021-10, Vol.12 (5), p.e0244621-e0244621 [Periódico revisado por pares]

United States: American Society for Microbiology

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Título:
Preclinical Evaluation of Recombinant Microbial Glycoside Hydrolases in the Prevention of Experimental Invasive Aspergillosis
Autor: Ostapska, Hanna ; Raju, Deepa ; Lehoux, Melanie ; Lacdao, Ira ; Gilbert, Stephanie ; Sivarajah, Piyanka ; Bamford, Natalie C ; Baker, Perrin ; Nguyen, Thi Tuyet Mai ; Zacharias, Caitlin A ; Gravelat, Fabrice N ; Howell, P Lynne ; Sheppard, Donald C
Chowdhary, Anuradha
Assuntos: Animals ; Antifungal Agents - administration & dosage ; Antifungal Agents - pharmacokinetics ; Aspergillus fumigatus - pathogenicity ; Biofilms - drug effects ; Biofilms - growth & development ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Female ; Glycoside Hydrolases - administration & dosage ; Glycoside Hydrolases - genetics ; Glycoside Hydrolases - pharmacokinetics ; Invasive Pulmonary Aspergillosis - microbiology ; Invasive Pulmonary Aspergillosis - prevention & control ; Mice ; Mice, Inbred BALB C ; Mycology ; Neutropenia ; Recombinant Proteins - administration & dosage ; Recombinant Proteins - genetics ; Research Article ; Virulence
É parte de: mBio, 2021-10, Vol.12 (5), p.e0244621-e0244621
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Hanna Ostapska and Deepa Raju contributed equally. Hanna Ostapska was placed first for writing the manuscript.
Present address: Melanie Lehoux, Department of Pathology and Immunology, University of Montreal, Montreal, Canada; Stephanie Gilbert, Department of Molecular and Cellular Biology, University of Guelph, Guelph, Canada; Natalie C. Bamford, Division of Molecular Microbiology, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
Descrição: Aspergillus fumigatus is a ubiquitous mold that can cause invasive pulmonary infections in immunocompromised patients. Within the lung, A. fumigatus forms biofilms that can enhance resistance to antifungals and immune defenses. Aspergillus biofilm formation requires the production of a cationic matrix exopolysaccharide, galactosaminogalactan (GAG). In this study, recombinant glycoside hydrolases (GH)s that degrade GAG were evaluated as antifungal agents in a mouse model of invasive aspergillosis. Intratracheal GH administration was well tolerated by mice. Pharmacokinetic analysis revealed that although GHs have short half-lives, GH prophylaxis resulted in reduced fungal burden in leukopenic mice and improved survival in neutropenic mice, possibly through augmenting pulmonary neutrophil recruitment. Combining GH prophylaxis with posaconazole treatment resulted in a greater reduction in fungal burden than either agent alone. This study lays the foundation for further exploration of GH therapy in invasive fungal infections. The biofilm-forming mold Aspergillus fumigatus is a common causative agent of invasive fungal airway disease in patients with a compromised immune system or chronic airway disease. Treatment of A. fumigatus infection is limited by the few available antifungals to which fungal resistance is becoming increasingly common. The high mortality rate of A. fumigatus-related infection reflects a need for the development of novel therapeutic strategies. The fungal biofilm matrix is in part composed of the adhesive exopolysaccharide galactosaminogalactan, against which antifungals are less effective. Previously, we demonstrated antibiofilm activity with recombinant forms of the glycoside hydrolase enzymes that are involved in galactosaminogalactan biosynthesis. In this study, prophylaxis with glycoside hydrolases alone or in combination with the antifungal posaconazole in a mouse model of experimental aspergillosis improved outcomes. This study offers insight into the therapeutic potential of combining biofilm disruptive agents to leverage the activity of currently available antifungals.
Editor: United States: American Society for Microbiology
Idioma: Inglês

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Preclinical Evaluation of Recombinant Microbial Glycoside Hydrolases in the Prevention of Experimental Invasive Aspergillosis

Ostapska, Hanna ; Raju, Deepa ; Lehoux, Melanie ; Lacdao, Ira ; Gilbert, Stephanie ; Sivarajah, Piyanka ; Bamford, Natalie C ; Baker, Perrin ; Nguyen, Thi Tuyet Mai ; Zacharias, Caitlin A ; Gravelat, Fabrice N ; Howell, P Lynne ; Sheppard, Donald C Chowdhary, Anuradha

United States: American Society for Microbiology

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