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Anti-dormant mycobacterial activity and target molecule of melophlins, tetramic acid derivatives isolated from a marine sponge of Melophlus sp.

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  • Biologically Active Natural Products from Microorganisms and Plants
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Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis infection, is a major world health problem that is responsible for the deaths of 1.5 million people each year. In addition, the requirement for long-term therapy to cure TB complicates treatment of the disease. One of the major reasons for the extended chemotherapeutic regimens and wide epidemicity of TB is that M. tuberculosis has the ability to persist in a dormant state. We therefore established a new screening system to search for substances with activity against dormant mycobacteria using M. smegmatis and M. bovis BCG cultivated in medium containing propionate as sole carbon source to induce dormancy. Subsequently, melophlins A (1), G (2), H (3), and I (4), tetramic acid derivatives, were re-discovered from the Indonesian marine sponge of Melophlus sp. as anti-dormant mycobacterial substances. Moreover, target analysis of melophlin A indicated that it targeted the BCG1083 protein of putative exopolyphosphatase and the BCG1321c protein of diadenosine 5′,5‴-P1,P4-tetraphosphate phosphorylase.

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Acknowledgments

The authors are grateful to Drs. William R. Jacobs, Jr. and Catherine Vilchèze (Albert Einstein College of Medicine, New York, USA) for kindly providing the M. smegmatis mc2155 and M. bovis BCG Pasteur strains, and the pMV206, pMV261, and pYUB415 vectors, and for their support for the genomic DNA library. This study was financially supported by the Hoansha Foundation, the Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) and Japan Agency for Medical Research and Development (AMED), the Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science (JSPS) (15H03114, 26305002, and 24310159), and the Grant-in-Aid for Scientific Research on Innovative Areas from MEXT (23102005).

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    Authors and Affiliations

    1. Graduate School of Pharmaceutical Sciences, Osaka University, Yamada-oka 1-6, Suita, Osaka, 565-0871, Japan

      Masayoshi Arai, Yoshi Yamano, Kentaro Kamiya & Motomasa Kobayashi

    2. Department of Chemistry, Faculty of Science, Lampung University, Jl. Prof. Dr. Sumantri Brodjonegoro No. 1, Bandar Lampung, 35145, Indonesia

      Andi Setiawan

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    1. Masayoshi Arai
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    2. Yoshi Yamano
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    3. Kentaro Kamiya
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    5. Motomasa Kobayashi
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    Correspondence to Masayoshi Arai or Motomasa Kobayashi.

    Additional information

    This article is dedicated to Professor Satoshi Ōmura in celebration of his 2015 Nobel Prize.

    M. Arai and Y. Yamano contributed equally to this work.

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    Arai, M., Yamano, Y., Kamiya, K. et al. Anti-dormant mycobacterial activity and target molecule of melophlins, tetramic acid derivatives isolated from a marine sponge of Melophlus sp.. J Nat Med 70, 467–475 (2016). https://doi.org/10.1007/s11418-016-1005-1

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    • DOI: https://doi.org/10.1007/s11418-016-1005-1

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