Abstract
Buruli Ulcer (BU) is a cutaneous disease caused by Mycobacterium ulcerans. The pathogenesis of this disease is closely related to the secretion of the toxin mycolactone that induces extensive destruction of the skin and soft tissues. Currently, there are no effective measures to prevent the disease and, despite availability of antibiotherapy and surgical treatments, these therapeutic options are often associated with severe side effects. Therefore, it is important to develop alternative strategies for the treatment of BU. Endolysins (lysins) are phage encoded enzymes that degrade peptidoglycan of bacterial cell walls. Over the past years, lysins have been emerging as alternative antimicrobial agents against bacterial infections. However, mycobacteria have an unusual outer membrane composed of mycolylarabinogalactan-peptidoglycan. To overcome this complex barrier, some mycobacteriophages encode a lipolytic enzyme, Lysin B (LysB). In this study, we demonstrate for the first time that recombinant LysB displays lytic activity against M. ulcerans isolates. Moreover, using a mouse model of M. ulcerans footpad infection, we show that subcutaneous treatment with LysB prevented further bacterial proliferation, associated with IFN-γ and TNF production in the draining lymph node. These findings highlight the potential use of lysins as a novel therapeutic approach against this neglected tropical disease.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bacteriolysis
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Buruli Ulcer / drug therapy*
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Buruli Ulcer / pathology
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Disease Models, Animal
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Endopeptidases / administration & dosage*
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Endopeptidases / pharmacology
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Female
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Interferon-gamma / analysis
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Lymph Nodes / immunology
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Mice, Inbred BALB C
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Mycobacteriophages / enzymology*
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Mycobacterium ulcerans / drug effects*
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Mycobacterium ulcerans / virology
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Recombinant Proteins / administration & dosage
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Recombinant Proteins / pharmacology
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Treatment Outcome
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Tumor Necrosis Factor-alpha / analysis
Substances
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Recombinant Proteins
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Tumor Necrosis Factor-alpha
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Interferon-gamma
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Endopeptidases
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endolysin
Grants and funding
The project was developed within the scope of the projects NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement through FEDER. This work was also supported by BioTecNorte operation (NORTE-01-0145-FEDER -000004) funded by the European Regional Development Fund under the scope of NORTE 2020. This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit; the Competitiveness Factors Operational Programme (COMPETE 2020) projects POCI-01-0145-FEDER-006684 and POCI-01-0145-FEDER-007038; and the project PTDC/BBB-BSS/6471/2014 (POCI-01-0145-FEDER-016678). This study was also supported by Infect-ERA grant Infect-ERA/0002/2015: BU_SPONT_HEAL. AGF, GT, and HO would like to acknowledge FCT for the individual fellowships SFRH/BPD/112903/2015, SFRH/BPD/64032/2009, and SFRH/BPD/111653/2015, respectively. CMG received an individual QREN fellowship (UMINHO/BPD/15/2014). GangaGen acknowledges CSIR / OSDD, Govt of India, for funding this project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.