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      Honokiol, magnolol and its monoacetyl derivative show strong anti-fungal effect on Fusarium isolates of clinical relevance

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          Abstract

          The antifungal activity of magnolol and honokiol, two naturally occurring hydroxylated biphenyls, and of their synthetic derivatives was evaluated on a collection of representative isolates of Fusarium oxysporum, F. solani and F. verticillioides of clinical and ecological concern. The tested compounds were proposed as a ‘natural’ alternative to conventional fungicides, even though a larger range of concentrations (5–400 μg/ml) was applied. The activity of magnolol and honokiol was compared with that of terbinafine (0.1–10 μg/ml), and fluconazole (1–50 μg/ml), two fungicides widely used in treating fungal infections on humans. Magnolol showed similar fungicidal activity compared to fluconazole, whereas honokiol was more effective in inhibiting mycelium growth compared to this fungicide on all tested clinical Fusarium spp. isolates. Compared to terbinafine, honokiol showed similar antifungal activity when tested on clinical F. solani isolates, whereas magnolol was less effective at all selected concentrations (5–400 μg/ml). The different position of the phenol-OH group, as well as its protection, explain different in vitro activities between magnolol, honokiol, and their derivatives. Furthermore, magnolol showed mycelium dry weight reduction at a concentration of 0.5 mM when tested on a set of agricultural isolates of Fusaria, leading to complete inhibition of some of them. Magnolol and honokiol are proposed as efficient and safe candidates for treating clinically relevant Fusaria.

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          Most cited references36

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          Atroposelective total synthesis of axially chiral biaryl natural products.

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            Fusarium infections in immunocompromised patients.

            Fusarium species cause a broad spectrum of infections in humans, including superficial, locally invasive, and disseminated infections. The clinical form of fusariosis depends largely on the immune status of the host and the portal of entry, with superficial and localized disease occurring mostly in immunocompetent patients and invasive and disseminated disease affecting immunocompromised patients. Risk factors for severe fusariosis include prolonged neutropenia and T-cell immunodeficiency, especially in hematopoietic stem cell transplant recipients with severe graft-versus-host disease. The most frequent presentation of disseminated fusariosis is a combination of characteristic cutaneous lesions and positive blood cultures, with or without lung or sinus involvement. The prognosis is poor and is determined largely by degree of immunosuppression and extent of infection, with virtually a 100% death rate among persistently neutropenic patients with disseminated disease. These infections may be clinically suspected on the basis of a constellation of clinical and laboratory findings, which should lead to prompt therapy. Treatment options include the lipid formulations of amphotericin B, voriconazole, and posaconazole. Prevention of fusarial infection among high-risk patients should be considered.
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              Fusariosis, a complex infection caused by a high diversity of fungal species refractory to treatment.

              J. Guarro (2013)
              In recent years the number of opportunistic invasive fusariosis has increased significantly, the main factors involved in these infections being reviewed here. In spite of the extensive literature published the advances in the management of disseminated fusariosis have been very poor and it remains a severe infection, refractory to treatment and with a high mortality rate. There are no ideal therapies and the presence of neutropenia has a critical part to play in the outcome of the infection. At least 70 species have been involved in fusariosis. Fusarium solani species complex is responsible for nearly 60% of the cases and F. oxysporum species complex for approximately 20% of them. Most of the infections are caused by four species, i.e. F. petroliphilum, F. keratoplasticum and other two unnamed phylogenetic species. The efficacy of amphotericin B and voriconazole, the most used antifungal drugs, for treating invasive fusariosis are controversial but in general the percentage of patients cured in the different clinical trials is low. Infections by Fusarium verticillioides seem to have the best prognosis. The recent release of complete genome sequences of the most clinically relevant species and the emergence of fungal genomics offer excellent opportunities for examining the multifactorial processes of Fusarium pathogenicity. Using knockout mutants of genes encoding sequence-specific proteins, several virulence factors have been characterized.
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                Author and article information

                Contributors
                Role: Data curationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: SoftwareRole: ValidationRole: Visualization
                Role: Formal analysisRole: InvestigationRole: Methodology
                Role: Formal analysisRole: InvestigationRole: Methodology
                Role: ConceptualizationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: Methodology
                Role: Data curationRole: Formal analysisRole: Funding acquisitionRole: Methodology
                Role: Data curationRole: Formal analysisRole: Methodology
                Role: Funding acquisitionRole: Project administrationRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                4 September 2019
                2019
                : 14
                : 9
                : e0221249
                Affiliations
                [1 ] Dipartimento di Agraria, Sezione di Patologia Vegetale ed Entomologia and Unità di Ricerca Istituto Nazionale di Biostrutture e Biosistemi, Università degli Studi di Sassari, Viale Italia, Sassari, Italy
                [2 ] Istituto CNR di Chimica Biomolecolare, Traversa La Crucca, Sassari, Italy
                [3 ] Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)—Centro de Investigaciones de Fitopatología (CIDEFI-CIC-UNLP), Facultad de Ciencias Agrarias y Forestales, Universidad Nacional de La Plata, La Plata–Buenos Aires, Argentina
                Georg-August-Universitat Gottingen, GERMANY
                Author notes

                Competing Interests: Concerning submitted manuscript, authors declare having no conflict of interest relating to employment, consultancy, patents, products in development and marketed products with SIPCAM Italia SpA. SIPCAM Italia SpA is the commercial funder of Sara Ofensou's PhD grant and the submitted manuscript represents one part of SO's PhD work. In this context, SIPCAM Italia SpA has been properly acknowledged and nothing is further due. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0003-4766-7251
                http://orcid.org/0000-0001-8650-387X
                Article
                PONE-D-19-08132
                10.1371/journal.pone.0221249
                6726233
                31483823
                e44a20c5-3105-45c2-a9b2-6addbee1df70
                © 2019 Oufensou et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 21 March 2019
                : 4 August 2019
                Page count
                Figures: 2, Tables: 5, Pages: 16
                Funding
                S.O. acknowledges financial support from SIPCAM Italia S.p.A., CNR-CONICET Bilateral project 2016-2018, Fondazione Sardegna - Annualità 2016, and Regione Sardegna L.R. 7/12007 - Annualità 2016. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Microbiology
                Medical Microbiology
                Microbial Pathogens
                Fungal Pathogens
                Fusarium
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogens
                Microbial Pathogens
                Fungal Pathogens
                Fusarium
                Biology and Life Sciences
                Mycology
                Fungal Pathogens
                Fusarium
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Antimicrobials
                Antifungals
                Biology and Life Sciences
                Microbiology
                Microbial Control
                Antimicrobials
                Antifungals
                Biology and Life Sciences
                Mycology
                Antifungals
                Biology and Life Sciences
                Mycology
                Fungal Structure
                Mycelium
                Biology and Life Sciences
                Agriculture
                Agrochemicals
                Fungicides
                Biology and Life Sciences
                Organisms
                Eukaryota
                Fungi
                Biology and Life Sciences
                Anatomy
                Musculoskeletal System
                Body Limbs
                Legs
                Feet
                Toes
                Medicine and Health Sciences
                Anatomy
                Musculoskeletal System
                Body Limbs
                Legs
                Feet
                Toes
                Biology and Life Sciences
                Microbiology
                Medical Microbiology
                Microbial Pathogens
                Fungal Pathogens
                Fusarium
                Fusarium Oxysporum
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogens
                Microbial Pathogens
                Fungal Pathogens
                Fusarium
                Fusarium Oxysporum
                Biology and Life Sciences
                Mycology
                Fungal Pathogens
                Fusarium
                Fusarium Oxysporum
                Medicine and Health Sciences
                Infectious Diseases
                Fungal Diseases
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                All relevant data are within the manuscript and its Supporting Information files.

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