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Screening of diverse marine invertebrate extracts identified Lissoclinotoxin F, Discodermin B, and other anti-Mycobacterium tuberculosis active compounds

The Journal of Antibiotics volume 75, pages 213–225 (2022)Cite this article

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Abstract

Screening of a marine derived crude natural product extract library, followed by bioactivity guided fractionation, has led to isolation and structural elucidation of 10 natural products as hits active against Mycobacterium tuberculosis (Mtb). Among them, three (3, 4 and 5) were identified for the first time and the remaining 7 compounds (1, 2, 6, 7, 8, 9 and 10) were previously reported, but now assigned with anti-mycobacterial activity. Among identified hits, the oligo cyclic depsipeptide discodermin B (7) exhibited the highest potency with an MIC90 value of 0.5 µM. The polysufide alkaloid lissoclinotoxin F (1) displayed a good balance of anti Mtb potency (MIC90 = 2.6 µM) and selectivity (SI = 19 in HEK293 cells). Lissoclinotoxin F (1) was found to be active against intracellular Mtb as well as non-replicating forms of Mtb, with higher activity against Mtb compared to other gram-negative and gram-positive bacteria. Consequently, lissoclinotoxin F (1) could be used as a lead compound for development of new TB drugs. Details regarding screening techniques, structural elucidation and preliminary structural activity relationships (SAR) of the isolated hits are discussed.

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Acknowledgements

Funding for this work was provided by the Canadian Institute of Health Research PJT-148646 and PJT-152931.

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Authors and Affiliations

  1. Departments of Medicine and Microbiology and Immunology, Life Sciences Institute, University of British Columbia, V6T 1Z3, Vancouver, BC, Canada

    Henok A. Sahile, Mary Ko & Yossef Av-Gay

  2. Departments of Chemistry and Earth & Ocean Sciences, University of British Columbia, V6T 1Z1, Vancouver, BC, Canada

    David E. Williams & Raymond J. Andersen

  3. Netherlands Centre for Biodiversity Naturalis, P.O. Box 9517, 2300 RA, Leiden, The Netherlands

    Nicole J. de Voogd

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Sahile, H.A., Williams, D.E., de Voogd, N.J. et al. Screening of diverse marine invertebrate extracts identified Lissoclinotoxin F, Discodermin B, and other anti-Mycobacterium tuberculosis active compounds. J Antibiot 75, 213–225 (2022). https://doi.org/10.1038/s41429-022-00507-9

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