scholarly journals Antifungal siderophore conjugates for theranostic applications in invasive pulmonary aspergillosis using low molecular TAFC scaffolds

2021 ◽  
Author(s):  
Joachim Pfister ◽  
Milos Petrik ◽  
Katherina Bendova ◽  
Barbera Matuszczak ◽  
Ulrike Binder ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Aspergillus Fumigatus ◽  
Antifungal Susceptibility ◽  
Invasive Pulmonary Aspergillosis ◽  
Fungal Growth ◽  
Pulmonary Aspergillosis ◽  
Pet Ct ◽  
Susceptibility Tests ◽  
Fungal Growth Inhibition ◽  
Gallium 68

Invasive pulmonary aspergillosis (IPA) is a life-threatening form of fungal infection, primarily in immunocompromised patients and associated with a significant mortality. Diagnostic procedures are often invasive and/or time consuming and existing antifungals can be constrained by dose limiting toxicity and drug interaction. In this study, we modified triacetylfusarinine C (TAFC), the main siderophore produced by the opportunistic pathogen Aspergillus fumigatus, with antifungal molecules to perform antifungal susceptibility tests and molecular imaging. Methods: A variation of small organic molecules (eflornithine, fludioxonil, thiomersal, fluoroorotic acid (FOA), cyanine 5 (Cy5)) with antifungal activity were coupled to TAFC, resulting in a Trojan horse to deliver antifungal compounds specifically into Aspergillus fumigatus hyphae by the major facilitator transporter MirB. Radioactive labelling with gallium-68 allowed to perform in vitro characterization (LogD, stability, uptake assay) as well as biodistribution experiments and PET/CT imaging in an IPA rat infection model. Compounds labelled with stable gallium were used for antifungal susceptibility tests. Results: [Ga]DAFC-fludioxonil, -FOA and Cy5 revealed a MirB dependent active uptake with fungal growth inhibition at 16 μg/mL after 24 h. Visualization of an Aspergillus fumigatus infection in lungs of a rat was possible with gallium-68 labelled compounds using PET/CT. Heterogeneous biodistribution patterns revealed the immense influence of the antifungal moiety conjugated to DAFC. Conclusion: Overall, novel antifungal siderophore conjugates with promising fungal growth inhibition and the possibility to perform PET-imaging, combine both therapeutic and diagnostic potential in a theranostic compound for IPA caused by Aspergillus fumigatus.

scholarly journals Antifungal Siderophore Conjugates for Theranostic Applications in Invasive Pulmonary Aspergillosis Using Low-Molecular TAFC Scaffolds

2021 ◽  
Vol 7 (7) ◽  
pp. 558
Author(s):  
Joachim Pfister ◽  
Milos Petrik ◽  
Katerina Bendova ◽  
Barbara Matuszczak ◽  
Ulrike Binder ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Antifungal Susceptibility ◽  
Invasive Pulmonary Aspergillosis ◽  
Fungal Growth ◽  
Pulmonary Aspergillosis ◽  
Diagnostic Potential ◽  
Pet Ct ◽  
Susceptibility Tests ◽  
Fungal Growth Inhibition ◽  
Gallium 68

Invasive pulmonary aspergillosis (IPA) is a life-threatening form of fungal infection, primarily in immunocompromised patients and associated with significant mortality. Diagnostic procedures are often invasive and/or time consuming and existing antifungals can be constrained by dose-limiting toxicity and drug interaction. In this study, we modified triacetylfusarinine C (TAFC), the main siderophore produced by the opportunistic pathogen Aspergillus fumigatus (A. fumigatus), with antifungal molecules to perform antifungal susceptibility tests and molecular imaging. A variation of small organic molecules (eflornithine, fludioxonil, thiomersal, fluoroorotic acid (FOA), cyanine 5 (Cy5) with antifungal activity were coupled to diacetylfusarinine C (DAFC), resulting in a “Trojan horse” to deliver antifungal compounds specifically into A. fumigatus hyphae by the major facilitator transporter MirB. Radioactive labeling with gallium-68 allowed us to perform in vitro characterization (distribution coefficient, stability, uptake assay) as well as biodistribution experiments and PET/CT imaging in an IPA rat infection model. Compounds chelated with stable gallium were used for antifungal susceptibility tests. [Ga]DAFC-fludioxonil, -FOA, and -Cy5 revealed a MirB-dependent active uptake with fungal growth inhibition at 16 µg/mL after 24 h. Visualization of an A. fumigatus infection in lungs of a rat was possible with gallium-68-labeled compounds using PET/CT. Heterogeneous biodistribution patterns revealed the immense influence of the antifungal moiety conjugated to DAFC. Overall, novel antifungal siderophore conjugates with promising fungal growth inhibition and the possibility to perform PET imaging combine both therapeutic and diagnostic potential in a theranostic compound for IPA caused by A. fumigatus.

scholarly journals Three-Dimensional Light Sheet Fluorescence Microscopy of Lungs To Dissect Local Host Immune-Aspergillus fumigatus Interactions

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jorge Amich ◽  
Zeinab Mokhtari ◽  
Marlene Strobel ◽  
Elena Vialetto ◽  
Dalia Sheta ◽  
...  
Keyword(s):  
Animal Models ◽  
Fluorescence Microscopy ◽  
Aspergillus Fumigatus ◽  
Invasive Pulmonary Aspergillosis ◽  
Fungal Growth ◽  
Light Sheet ◽  
Murine Models ◽  
Pulmonary Aspergillosis ◽  
Content Type ◽  
Light Sheet Fluorescence Microscopy

ABSTRACT Aspergillus fumigatus is an opportunistic fungal pathogen that can cause life-threatening invasive lung infections in immunodeficient patients. The cellular and molecular processes of infection during onset, establishment, and progression of A. fumigatus infections are highly complex and depend on both fungal attributes and the immune status of the host. Therefore, preclinical animal models are of paramount importance to investigate and gain better insight into the infection process. Yet, despite their extensive use, commonly employed murine models of invasive pulmonary aspergillosis are not well understood due to analytical limitations. Here, we present quantitative light sheet fluorescence microscopy (LSFM) to describe fungal growth and the local immune response in whole lungs at cellular resolution within its anatomical context. We analyzed three very common murine models of pulmonary aspergillosis based on immunosuppression with corticosteroids, chemotherapy-induced leukopenia, or myeloablative irradiation. LSFM uncovered distinct architectures of fungal growth and degrees of tissue invasion in each model. Furthermore, LSFM revealed the spatial distribution, interaction, and activation of two key immune cell populations in antifungal defense: alveolar macrophages and polymorphonuclear neutrophils. Interestingly, the patterns of fungal growth correlated with the detected effects of the immunosuppressive regimens on the local immune cell populations. Moreover, LSFM demonstrates that the commonly used intranasal route of spore administration did not result in complete intra-alveolar deposition, as about 80% of fungal growth occurred outside the alveolar space. Hence, characterization by LSFM is more rigorous than by previously used methods employing murine models of invasive pulmonary aspergillosis and pinpoints their strengths and limitations. IMPORTANCE The use of animal models of infection is essential to advance our understanding of the complex host-pathogen interactions that take place during Aspergillus fumigatus lung infections. As in the case of humans, mice need to suffer an immune imbalance in order to become susceptible to invasive pulmonary aspergillosis (IPA), the most serious infection caused by A. fumigatus. There are several immunosuppressive regimens that are routinely used to investigate fungal growth and/or immune responses in murine models of invasive pulmonary aspergillosis. However, the precise consequences of the use of each immunosuppressive model for the local immune populations and for fungal growth are not completely understood. Here, to pin down the scenarios involving commonly used IPA models, we employed light sheet fluorescence microscopy (LSFM) to analyze whole lungs at cellular resolution. Our results will be valuable to optimize and refine animal models to maximize their use in future research.

Fungal Growth Inhibition by Cheese Prepared Using Milk-clotting Crude Enzymes from the Edible Mushroom Hericium erinaceum

2020 ◽  
Vol 26 (1) ◽  
pp. 93-99
Author(s):  
Munekazu Kishimoto ◽  
Kazuo Nakamura ◽  
Takuto Tasaki ◽  
Kinya Matsumoto ◽  
Rina Nakano ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Fungal Growth ◽  
Edible Mushroom ◽  
Milk Clotting ◽  
Hericium Erinaceum ◽  
Fungal Growth Inhibition

scholarly journals Novel Bifunctional Inhibitor of Xylanase and Aspartic Protease: Implications for Inhibition of Fungal Growth

2001 ◽  
Vol 45 (7) ◽  
pp. 2008-2017 ◽  
Author(s):  
Chandravanu Dash ◽  
Absar Ahmad ◽  
Devyani Nath ◽  
Mala Rao
Keyword(s):  
Growth Inhibition ◽  
Fungal Growth ◽  
Phytopathogenic Fungi ◽  
Aspartic Protease ◽  
Cellular Growth ◽  
Alternative Mechanism ◽  
Trinitrobenzenesulfonic Acid ◽  
Woodward’S Reagent K ◽  
Bifunctional Inhibitor ◽  
Fungal Growth Inhibition

ABSTRACT A novel bifunctional inhibitor (ATBI) from an extremophilicBacillus sp. exhibiting an activity against phytopathogenic fungi, including Alternaria, Aspergillus, Curvularia, Colletotricum, Fusarium, and Phomopsis species, and the saprophytic fungus Trichoderma sp. has been investigated. The 50% inhibitory concentrations of ATBI ranged from 0.30 to 5.9 μg/ml, whereas the MIC varied from 0.60 to 3.5 μg/ml for the fungal growth inhibition. The negative charge and the absence of periodic secondary structure in ATBI suggested an alternative mechanism for fungal growth inhibition. Rescue of fungal growth inhibition by the hydrolytic products of xylanase and aspartic protease indicated the involvement of these enzymes in cellular growth. The chemical modification of Asp or Glu or Lys residues of ATBI by 2,4,6-trinitrobenzenesulfonic acid and Woodward's reagent K, respectively, abolished its antifungal activity. In addition, ATBI also inhibited xylanase and aspartic protease competitively, withKi values 1.75 and 3.25 μM, respectively. Our discovery led us to envisage a paradigm shift in the concept of fungal growth inhibition for the role of antixylanolytic activity. Here we report for the first time a novel class of antifungal peptide, exhibiting bifunctional inhibitory activity.

scholarly journals COVID-19 Associated Invasive Pulmonary Aspergillosis: Diagnostic and Therapeutic Challenges

2020 ◽  
Vol 6 (3) ◽  
pp. 115 ◽  
Author(s):  
Aia Mohamed ◽  
Thomas R. Rogers ◽  
Alida Fe Talento
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Distress Syndrome ◽  
Susceptibility Testing ◽  
Antifungal Susceptibility ◽  
Invasive Pulmonary Aspergillosis ◽  
Case Definition ◽  
Pulmonary Aspergillosis ◽  
Diagnostic Screening ◽  
Definition Of ◽  
Clinical Awareness

Aspergillus co-infection in patients with severe coronavirus disease 2019 (COVID-19) pneumonia, leading to acute respiratory distress syndrome, has recently been reported. To date, 38 cases have been reported, with other cases most likely undiagnosed mainly due to a lack of clinical awareness and diagnostic screening. Importantly, there is currently no agreed case definition of COVID-19 associated invasive pulmonary aspergillosis (CAPA) that could aid in the early detection of this co-infection. Additionally, with the global emergence of triazole resistance, we emphasize the importance of antifungal susceptibility testing in order to ensure appropriate antifungal therapy. Herein is a review of 38 published CAPA cases, which highlights the diagnostic and therapeutic challenges posed by this novel fungal co-infection.

scholarly journals Competitive Exclusion Is a Major Bioprotective Mechanism of Lactobacilli against Fungal Spoilage in Fermented Milk Products

2020 ◽  
Vol 86 (7) ◽  
Author(s):  
Solvej Siedler ◽  
Martin Holm Rau ◽  
Susanne Bidstrup ◽  
Justin M. Vento ◽  
Stina Dissing Aunsbjerg ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Dairy Products ◽  
Molecular Mechanisms ◽  
Competitive Exclusion ◽  
Defense Mechanism ◽  
Fungal Growth ◽  
Fermented Milk ◽  
Attractive Alternative ◽  
Spoilage Yeast ◽  
Fungal Growth Inhibition

ABSTRACT A prominent feature of lactic acid bacteria (LAB) is their ability to inhibit growth of spoilage organisms in food, but hitherto research efforts to establish the mechanisms underlying bioactivity focused on the production of antimicrobial compounds by LAB. We show, in this study, that competitive exclusion, i.e., competition for a limited resource by different organisms, is a major mechanism of fungal growth inhibition by lactobacilli in fermented dairy products. The depletion of the essential trace element manganese by two Lactobacillus species was uncovered as the main mechanism for growth inhibition of dairy spoilage yeast and molds. A manganese transporter (MntH1), representing one of the highest expressed gene products in both lactobacilli, facilitates the exhaustive manganese scavenging. Expression of the mntH1 gene was found to be strain dependent, affected by species coculturing and the growth phase. Further, deletion of the mntH1 gene in one of the strains resulted in a loss of bioactivity, proving this gene to be important for manganese depletion. The presence of an mntH gene displayed a distinct phylogenetic pattern within the Lactobacillus genus. Moreover, assaying the bioprotective ability in fermented milk of selected lactobacilli from 10 major phylogenetic groups identified a correlation between the presence of mntH and bioprotective activity. Thus, manganese scavenging emerges as a common trait within the Lactobacillus genus, but differences in expression result in some strains showing more bioprotective effect than others. In summary, competitive exclusion through ion depletion is herein reported as a novel mechanism in LAB to delay the growth of spoilage contaminants in dairy products. IMPORTANCE In societies that have food choices, conscious consumers demand natural solutions to keep their food healthy and fresh during storage, simultaneously reducing food waste. The use of “good bacteria” to protect food against spoilage organisms has a long, successful history, even though the molecular mechanisms are not fully understood. In this study, we show that the depletion of free manganese is a major bioprotective mechanism of lactobacilli in dairy products. High manganese uptake and intracellular storage provide a link to the distinct, nonenzymatic, manganese-catalyzed oxidative stress defense mechanism, previously described for certain lactobacilli. The evaluation of representative Lactobacillus species in our study identifies multiple relevant species groups for fungal growth inhibition via manganese depletion. Hence, through the natural mechanism of nutrient depletion, the use of dedicated bioprotective lactobacilli constitutes an attractive alternative to artificial preservation.

scholarly journals An automated quantitative assay for fungal growth inhibition

1990 ◽  
Vol 69 (1-2) ◽  
pp. 55-59 ◽  
Author(s):  
Willem F. Broekaert ◽  
Frankt R.G. Terras ◽  
Bruno P.A. Cammue ◽  
Jos Vanderleyden
Keyword(s):  
Growth Inhibition ◽  
Fungal Growth ◽  
Quantitative Assay ◽  
Fungal Growth Inhibition

scholarly journals Evaluation of a commercial quantitative Aspergillus fumigatus-specific IgM assay for the diagnosis of invasive pulmonary aspergillosis

Medicine ◽  
2017 ◽  
Vol 96 (51) ◽  
pp. e9436 ◽  
Author(s):  
Yake Yao ◽  
Hua Zhou ◽  
Yihong Shen ◽  
Qing Yang ◽  
Jian Ye ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Invasive Pulmonary Aspergillosis ◽  
Pulmonary Aspergillosis

scholarly journals Effect of volatile organic compounds mediated fungal growth inhibition by Trichoderma asperellum HbGT6-07

2021 ◽  
Author(s):  
Md Kamaruzzaman ◽  
Md. Samiul Islam ◽  
Shakil Ahmed Polash ◽  
Razia Sultana
Keyword(s):  
Volatile Organic Compounds ◽  
Growth Inhibition ◽  
Botrytis Cinerea ◽  
Organic Compounds ◽  
Sclerotinia Sclerotiorum ◽  
Mycelial Growth ◽  
Fungal Growth ◽  
Trichoderma Asperellum ◽  
Volatile Organic ◽  
Fungal Growth Inhibition

Abstract The species of Trichoderma are one of the most frequently used natural biocontrol agents to mitigate plant diseases and improve crop yields. In this study, sixteen Trichoderma spp. were isolated from soil of different regions of China. However, we identified Trichoderma. asperellum HbGT6-07 by initial fungal growth inhibition assay and molecular approach and also evaluated the antimicrobial effects. Tested 10% concentrated culture filtrate of T. asperellum HbGT6-07 inhibited 93 % of colony radial growth in Botrytis cinerea (B05.10) as well as 91 % of Sclerotinia sclerotiorum (A367). VOCs emitted from HbGT6-07 have antimicrobial properties against Botrytis cinerea (B05.10) and Sclerotinia sclerotiorum (A367). In in-vitro DwD method, The T. asperellum HbGT6-07 volatile organic compounds (VOCs) effectively reduced colonial diameter, mycelial growth rate and sclerotia production by two virulent fungal pathogens. The GC-MS analysis identified thirty-two VOCs derived from HbGT6-07 isolates. Moreover, the hyphal fragments of the T. asperellum HbGT6-07 demonstrated successful mycelia growth suppression of two virulent fungal agents by competing toward the invasion on oilseed rape leaves. The above findings indicated that T. asperellum HbGT6-07 could attain competitive progress via volatile antifungal compound production and comprehensive mycelial growth. This study provided an outlook of using T. asperellum HbGT6-07 to control virulent pathogens of B. cinerea and S. sclerotiorum.

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