PT - JOURNAL ARTICLE AU - Alexandra G. Fraga AU - Gabriela Trigo AU - Juan Dominguez AU - Rita Silva-Gomes AU - Carine M. Gonçalves AU - Oliveira Hugo AU - António G. Castro AU - Joana Azeredo AU - Jorge Pedrosa TI - Antimicrobial activity of Mycobacteriophage D29 Lysin B during <em>Mycobacterium ulcerans</em> infection AID - 10.1101/507129 DP - 2018 Jan 01 TA - bioRxiv PG - 507129 4099 - http://biorxiv.org/content/early/2018/12/27/507129.short 4100 - http://biorxiv.org/content/early/2018/12/27/507129.full AB - 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. Although the World Health Organization recommends a combination of rifampicin and streptomycin for the treatment of BU, clinical management of advanced stages often requires extensive surgical resection of the infected tissue. 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 Gram-positive bacteria. Amongst Gram-positive bacteria, mycobacteria have an unusual outer membrane that is covalently attached to the mycolylarabinogalactan-peptidoglycan complex. To overcome this additional barrier to phage-mediated lysis, some mycobacteriophages encode a lipolytic enzyme, Lysin B (Lys B).In this study, we demonstrated for the first time that recombinant Lys B displays lytic activity against M. ulcerans isolates. Moreover, using a mouse model of M. ulcerans footpad infection, we show that subcutaneous treatment with Lys B leads to a reduction in bacterial burdens, 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.AUTHOR SUMMARY Buruli Ulcer (BU) is a necrotizing skin disease caused by Mycobacterium ulcerans. Standard treatment for BU lesions consists of a combination of rifampicin and streptomycin for 8 weeks. However, clinical management of advanced stages of the disease often requires extensive surgical resection of the infected tissue. Therefore, it is important to develop alternative strategies for the treatment of BU. In that sense, we tested the efficacy of Lysin B (Lys B), a phage encoded lipolytic enzyme that degrades the mycolylarabinogalactan-peptidoglycan complex present in the mycobacterial cell wall. In this study, we show that Lys B not only displays lytic activity against M. ulcerans isolates in vitro, but also leads to a reduction in bacterial burdens in M. ulcerans-infected mouse footpads. These findings highlight the potential use of lysins as a novel therapeutic approach against this neglected tropical disease.