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      In vivo experiments demonstrate the potent antileishmanial efficacy of repurposed suramin in visceral leishmaniasis

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          Treatment failure and resistance to the commonly used drugs remains a major obstacle for successful chemotherapy against visceral leishmaniasis (VL). Since the development of novel therapeutics involves exorbitant costs, the effectiveness of the currently available antitrypanosomatid drug suramin has been investigated as an antileishmanial, specifically for VL, in vitro and in animal model experiments.

          Methodology/Principal

          Leishmania donovani promastigotes were treated with suramin and studies were performed to determine the extent and mode of cell mortality, cell cycle arrest and other in vitro parameters. In addition, L. donovani infected BALB/c mice were administered suramin and a host of immunological parameters determined to estimate the antileishmanial potency of the drug. Finally, isothermal titration calorimetry (ITC) and enzymatic assays were used to probe the interaction of the drug with one of its putative targets namely parasitic phosphoglycerate kinase (LmPGK).

          Findings

          The in vitro studies revealed the potential efficacy of suramin against the Leishmania parasite. This observation was further substantiated in the in vivo murine model, which demonstrated that upon suramin administration, the Leishmania infected BALB/c mice were able to reduce the parasitic burden and also generate the host protective immunological responses. ITC and enzyme assays confirmed the binding and consequent inhibition of LmPGK due to the drug.

          Conclusions/Significance

          All experiments affirmed the efficacy of suramin against L. donovani infection, which could possibly lead to its inclusion in the repertoire of drugs against VL.

          Author summary

          Visceral Leishmaniasis (VL) or Kala-azar, classed as a neglected tropical disease, is still a major problem worldwide, aggravated by increasing parasitic resistance against the drugs commonly used for its treatment. Since the development of novel therapeutics involves exorbitant costs, the effectiveness of the currently available antitrypanosomatid drug suramin has been investigated as an antileishmanial, specifically for VL, in vitro and in animal model experiments. Our study showed that suramin is effective against L. donovani and significantly reduced the (splenic/hepatic) parasitic burden in L. donovani infected BALB/c mice, switching the immune response in the infected BALB/c mice from T H2 to a T H1 type. The ITC data confirmed that suramin does indeed interact with parasitic phosphoglycerate kinase (LmPGK) and enzyme assays demonstrated the inhibition of LmPGK due to the drug. Therefore, our investigation raises the possibility of suramin being included in the repertoire of drugs used to treat VL.

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          Most cited references 46

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          Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia.

          Cancer cells generally exhibit increased glycolysis for ATP generation (the Warburg effect) due in part to mitochondrial respiration injury and hypoxia, which are frequently associated with resistance to therapeutic agents. Here, we report that inhibition of glycolysis severely depletes ATP in cancer cells, especially in clones of cancer cells with mitochondrial respiration defects, and leads to rapid dephosphorylation of the glycolysis-apoptosis integrating molecule BAD at Ser(112), relocalization of BAX to mitochondria, and massive cell death. Importantly, inhibition of glycolysis effectively kills colon cancer cells and lymphoma cells in a hypoxic environment in which the cancer cells exhibit high glycolytic activity and decreased sensitivity to common anticancer agents. Depletion of ATP by glycolytic inhibition also potently induced apoptosis in multidrug-resistant cells, suggesting that deprivation of cellular energy supply may be an effective way to overcome multidrug resistance. Our study shows a promising therapeutic strategy to effectively kill cancer cells and overcome drug resistance. Because the Warburg effect and hypoxia are frequently seen in human cancers, these findings may have broad clinical implications.
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            The early interaction of Leishmania with macrophages and dendritic cells and its influence on the host immune response

            The complicated interactions between Leishmania and the host antigen-presenting cells (APCs) have fundamental effects on the final outcome of the disease. Two major APCs, macrophages and dendritic cells (DCs), play critical roles in mediating resistance and susceptibility during Leishmania infection. Macrophages are the primary resident cell for Leishmania: they phagocytose and permit parasite proliferation. However, these cells are also the major effector cells to eliminate infection. The effective clearance of parasites by macrophages depends on activation of appropriate immune response, which is usually initiated by DCs. Here, we review the early interaction of APCs with Leishmania parasites and how these interactions profoundly impact on the ensuing adaptive immune response. We also discuss how the current knowledge will allow further refinement of our understanding of the interplay between Leishmania and its hosts that leads to resistance or susceptibility.
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              Mechanism of amphotericin B resistance in clinical isolates of Leishmania donovani.

              The clinical value of amphotericin B, the mainstay therapy for visceral leishmaniasis in sodium antimony gluconate-nonresponsive zones of Bihar, India, is now threatened by the emergence of acquired drug resistance, and a comprehensive understanding of the underlying mechanisms is the need of the hour. We have selected an amphotericin B-resistant clinical isolate which demonstrated 8-fold-higher 50% lethal doses (LD(50)) than an amphotericin B-sensitive strain to explore the mechanism of amphotericin B resistance. Fluorimetric analysis demonstrated lower anisotropy in the motion of the diphenylhexatriene fluorescent probe in the resistant strain, which indicated a higher fluidity of the membrane for the resistant strain than for the sensitive strain. The expression patterns of the two transcripts of S-adenosyl-l-methionine:C-24-Δ-sterol methyltransferase and the absence of ergosterol, replaced by cholesta-5,7,24-trien-3β-ol in the membrane of the resistant parasite, indicate a decreased amphotericin B affinity, which is evidenced by decreased amphotericin B uptake. The expression level of MDR1 is found to be higher in the resistant strain, suggesting a higher rate of efflux of amphotericin B. The resistant parasite also possesses an upregulated tryparedoxin cascade and a more-reduced intracellular thiol level, which helps in better scavenging of reactive oxygen species produced by amphotericin B. The resistance to amphotericin B was partially reverted by the thiol metabolic pathway and ABC transporter inhibitors. Thus, it can be concluded that altered membrane composition, ATP-binding cassette transporters, and an upregulated thiol metabolic pathway have a role in conferring amphotericin B resistance in clinical isolates of Leishmania donovani.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Investigation
                Role: Data curationRole: InvestigationRole: Writing – review & editing
                Role: Data curation
                Role: Data curation
                Role: Data curation
                Role: Resources
                Role: Formal analysisRole: InvestigationRole: Supervision
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: Project administrationRole: SupervisionRole: 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
                31 August 2020
                August 2020
                : 14
                : 8
                Affiliations
                [1 ] Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, Bidhannagar, Kolkata India
                [2 ] Division of Molecular Medicine, Bose Institute, Kolkata, India
                [3 ] School of Biotechnology, Department of Life Sciences, Presidency University-New Campus, Kolkata, India
                [4 ] Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Bidhannagar, Kolkata, India
                [5 ] Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Kolkata, India
                [6 ] Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata, India
                [7 ] Homi Bhabha National Institute, Anushakti Nagar, Mumbai, India
                Ohio State University, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Article
                PNTD-D-19-01975
                10.1371/journal.pntd.0008575
                7491717
                32866156
                © 2020 Khanra 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.

                Page count
                Figures: 10, Tables: 1, Pages: 20
                Product
                Funding
                Funded by: Department of Atomic Energy, Government of India
                Award ID: SINP:-MSACR [XII-R&D-SIN-5.04-0102]
                Award Recipient :
                The work reported in the manuscript has been supported by the intramural grants from Department of Atomic Energy, Government of India (Projects of SINP:-MSACR [XII-R&D-SIN-5.04-0102]). 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
                Developmental Biology
                Life Cycles
                Protozoan Life Cycles
                Promastigotes
                Biology and Life Sciences
                Microbiology
                Protozoology
                Protozoan Life Cycles
                Promastigotes
                Medicine and Health Sciences
                Medical Conditions
                Parasitic Diseases
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Death
                Apoptosis
                Biology and Life Sciences
                Physiology
                Immune Physiology
                Cytokines
                Biology and Life Sciences
                Immunology
                Immune System
                Innate Immune System
                Cytokines
                Medicine and Health Sciences
                Immunology
                Immune System
                Innate Immune System
                Cytokines
                Biology and Life Sciences
                Developmental Biology
                Molecular Development
                Cytokines
                Medicine and Health Sciences
                Medical Conditions
                Tropical Diseases
                Neglected Tropical Diseases
                Leishmaniasis
                Medicine and Health Sciences
                Medical Conditions
                Parasitic Diseases
                Protozoan Infections
                Leishmaniasis
                Medicine and Health Sciences
                Medical Conditions
                Infectious Diseases
                Zoonoses
                Leishmaniasis
                Medicine and Health Sciences
                Pharmaceutics
                Drug Therapy
                Research and Analysis Methods
                Spectrum Analysis Techniques
                Spectrophotometry
                Cytophotometry
                Flow Cytometry
                Biology and Life Sciences
                Organisms
                Eukaryota
                Protozoans
                Parasitic Protozoans
                Leishmania
                Leishmania Donovani
                Custom metadata
                vor-update-to-uncorrected-proof
                2020-09-15
                All relevant data are within the manuscript and its Supporting Information files.

                Infectious disease & Microbiology

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