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      Antifungal activity of two oxadiazole compounds for the paracoccidioidomycosis treatment

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          Abstract

          Paracoccidioidomycosis (PCM) is a neglected disease present in Latin America with difficulty in treatment and occurrence of serious sequelae. Thus, the development of alternative therapies is imperative. In the current work, two oxadiazole compounds (LMM5 and LMM11) presented fungicidal activity against Paracoccidioides spp. The minimum inhibitory and fungicidal concentration values ranged from 1 to 32 μg/mL, and a synergic effect was observed for both compounds when combined with Amphotericin B. LMM5 and LMM11 were able to reduce CFU counts (≥2 log 10) on the 5 th and 7 th days of time-kill curve, respectively. The fungicide effect was confirmed by fluorescence microscopy (FUN-1/FUN-2). The hippocratic screening and biochemical analysis were performed in Balb/c male mice that received a high dose of each compound, and the compounds showed no in vivo toxicity. The treatment of experimental PCM with the new oxadiazoles led to significant reduction in CFU (≥1 log 10). Histopathological analysis of the groups treated exhibited control of inflammation, as well as preserved lung areas. These findings suggest that LMM5 and LMM11 are promising hits structures, opening the door for implementing new PCM therapies.

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          Paracoccidioidomycosis (PCM) is a granulomatous fungal infection with clinically severe forms and serious pulmonary sequelae. The current limited arsenal and prolonged treatment regimen demonstrate the need for new antifungals. This study reveals two fungicidal oxadiazole compounds for PCM treatment. The in vitro assay showed the antifungal activity and the synergic effect with Amphotericin B. The high doses administration in mice showed absence of toxicity, which allowed to demonstrate the in vivo antifungal activity.

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          Most cited references41

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          Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study.

          Inadequate antimicrobial treatment is an independent determinant of hospital mortality, and fungal bloodstream infections are among the types of infection with the highest rates of inappropriate initial treatment. Because of significant potential for reducing high mortality rates, we sought to assess the impact of delayed treatment across multiple study sites. The goals our analyses were to establish the frequency and duration of delayed antifungal treatment and to evaluate the relationship between treatment delay and mortality. We conducted a retrospective cohort study of patients with candidemia from 4 medical centers who were prescribed fluconazole. Time to initiation of fluconazole therapy was calculated by subtracting the date on which fluconazole therapy was initiated from the culture date of the first blood sample positive for yeast. A total of 230 patients (51% male; mean age +/- standard deviation, 56 +/- 17 years) were identified; 192 of these had not been given prior treatment with fluconazole. Patients most commonly had nonsurgical hospital admission (162 patients [70%]) with a central line catheter (193 [84%]), diabetes (68 [30%]), or cancer (54 [24%]). Candida species causing infection included Candida albicans (129 patients [56%]), Candida glabrata (38 [16%]), Candida parapsilosis (25 [11%]), or Candida tropicalis (15 [7%]). The number of days to the initiation of antifungal treatment was 0 (92 patients [40%]), 1 (38 [17%]), 2 (33 [14%]) or > or = 3 (29 [12%]). Mortality rates were lowest for patients who began therapy on day 0 (14 patients [15%]) followed by patients who began on day 1 (9 [24%]), day 2 (12 [37%]), or day > or = 3 (12 [41%]) (P = .0009 for trend). Multivariate logistic regression was used to calculate independent predictors of mortality, which include increased time until fluconazole initiation (odds ratio, 1.42; P < .05) and Acute Physiology and Chronic Health Evaluation II score (1-point increments; odds ratio, 1.13; P < .05). A delay in the initiation of fluconazole therapy in hospitalized patients with candidemia significantly impacted mortality. New methods to avoid delays in appropriate antifungal therapy, such as rapid diagnostic tests or identification of unique risk factors, are needed.
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            Brazilian guidelines for the clinical management of paracoccidioidomycosis

            Abstract Paracoccidioidomycosis is a systemic fungal disease occurring in Latin America that is associated with rural environments and agricultural activities. However, the incidence and prevalence of paracoccidiodomycosis is underestimated because of the lack of compulsory notification. If paracoccidiodomycosis is not diagnosed and treated early and adequately, the endemic fungal infection could result in serious sequelae. While the Paracoccidioides brasiliensis ( P. brasiliensis ) complex has been known to be the causal agent of paracoccidiodomycosis, a new species, Paracoccidioides lutzii ( P. lutzii ), has been reported in Rondônia, where the disease has reached epidemic levels, and in the Central West and Pará. Accurate diagnoses and availability of antigens that are reactive with the patients’ sera remain significant challenges. Therefore, the present guidelines aims to update the first Brazilian consensus on paracoccidioidomycosis by providing evidence-based recommendations for bedside patient management. This consensus summarizes etiological, ecoepidemiological, molecular epidemiological, and immunopathological data, with emphasis on clinical, microbiological, and serological diagnosis and management of clinical forms and sequelae, as well as in patients with comorbidities and immunosuppression. The consensus also includes discussion of outpatient treatments, severe disease forms, disease prevalence among special populations and resource-poor settings, a brief review of prevention and control measures, current challenges and recommendations.
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              Comparison of methods used for assessing the viability and vitality of yeast cells.

              Determination of cell viability is the most commonly used method for assessing the impact of various types of stressors in toxicity research and in industrial microbiology studies. Viability is defined as a percentage of live cells in a whole population. Although cell death is one of the consequences of toxicity, chemical or physical factors may exert their toxic effects through a number of cellular alterations that may compromise cell ability to divide without necessarily leading to cell death. This aspect represents the term 'cell vitality' defined as physiological capabilities of cells. It is important to note that cell viability and cell vitality represent two different aspects of cell functions, and both are required for the estimation of the physiological state of a cell after exposure to various types of stressors and chemical or physical factors. In this paper, we introduced a classification of available methods for estimating both viability and vitality in Saccharomyces cerevisiae yeast cells (wild-type and Δsod1 mutant) in which the effects of selected oxidants causing oxidative stress is evaluated. We present the advantages as well as disadvantages of the selected methods and assess their usefulness in different types of research.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: Validation
                Role: Investigation
                Role: InvestigationRole: Validation
                Role: InvestigationRole: Validation
                Role: Formal analysisRole: Methodology
                Role: Methodology
                Role: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: ResourcesRole: Supervision
                Role: ConceptualizationRole: Funding acquisitionRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                4 June 2019
                June 2019
                : 13
                : 6
                : e0007441
                Affiliations
                [1 ] Department of Clinical and Biomedical Analysis, State University of Maringá, Maringá, Brazil
                [2 ] Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, Brazil
                [3 ] Department of Basic Health Sciences, State University of Maringá, Maringá, Brazil
                [4 ] Department of Cell Biology, Institute of Biological Sciences, University of Brasília, Brazil
                [5 ] LORIA, Lorraine University, Nancy, France
                University of Tennessee, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-3290-8577
                Article
                PNTD-D-18-01983
                10.1371/journal.pntd.0007441
                6548352
                31163021
                1efc45bd-c62a-433e-921a-7cf2ca1c6721
                © 2019 Rodrigues-Vendramini 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
                : 13 December 2018
                : 6 May 2019
                Page count
                Figures: 7, Tables: 3, Pages: 16
                Funding
                Funded by: Conselho Nacional de Desenvolvimento Científico e Tecnológico (BR)
                Award ID: 481446/2013-3
                Award Recipient :
                This study was funded by National Council for Scientific and Technological Development (CNPq) ( http://www.cnpq.br/) - Grant number 481446/2013-3 to ESK, CAPES and Fundação Araucária to FAVRV. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                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
                Agriculture
                Agrochemicals
                Fungicides
                Research and Analysis Methods
                Microscopy
                Light Microscopy
                Fluorescence Microscopy
                Biology and Life Sciences
                Organisms
                Eukaryota
                Fungi
                Paracoccidioides
                Medicine and Health Sciences
                Infectious Diseases
                Fungal Diseases
                Paracoccidioidomycosis
                Medicine and Health Sciences
                Tropical Diseases
                Neglected Tropical Diseases
                Paracoccidioidomycosis
                Biology and Life Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Inflammation
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Inflammation
                Biology and Life Sciences
                Mycology
                Fungal Structure
                Biology and Life Sciences
                Toxicology
                Toxicity
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Toxicology
                Toxicity
                Custom metadata
                All relevant data are within the manuscript and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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