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Isolation of nocobactin NAs as Notch signal inhibitors from Nocardia farcinica, a possibility of invasive evolution

The Journal of Antibiotics volume 74, pages 255–259 (2021)Cite this article

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Abstract

Notch signaling inhibitors with the potential of immune suppressor production by pathogenic bacteria for easy host infection were searched from extracts of Nocardia sp. Nocobactin NA-a (compound 1) and nocobactin NA-b (compound 2), which have been suggested as pathogenesis factors, were isolated from N. farcinica IFM 11523 isolated from the sputum of a Japanese patient with chronic bronchitis. Compounds 1 and 2 showed Notch inhibitory activities with IC50 values of 12.4 and 17.6 μM, respectively. Compound 1 and 2 decreased of Notch1 protein, Notch intracellular domain, and hairy and enhancer of split 1, which is a Notch signaling target protein. In addition, compounds 1 and 2 showed cytotoxicity against mouse macrophage-like cell line RAW264.7 with IC50 values of 18.9 and 21.1 μM, respectively. These results suggested that the Notch inhibitors production by pathogenic bacteria may increase pathogen infectivity.

Notch signaling coordinates numerous cellular processes such as embryonic development, differentiation processes, and tissue homeostasis in adult organ systems [8,9,10,11]. In addition, Notch has recently been recognized as an important regulator of immune cell development and function [12, 13]. In T-cell differentiation, membrane-bound Delta-like ligands or expression of Notch intracellular domain (NICD) were shown to enhance differentiation of T helper 1 (Th1) cells in vitro [14]. Inhibition of Notch signaling with γ-secretase inhibitor suppressed Th1 cell differentiation [15, 16]. In addition, Notch is critical for Th2 cell-mediated immunity in vivo [17]. Another report described NICD expression in regulatory T cells (Tregs), which suppress immune responses and assist in tissue repair, diminished their regulatory function, suggesting that Notch also indirectly promotes T-cell effector responses by inhibiting suppression of responses by Tregs [18]. The NF-κB signaling pathway is one of the important immune responses in Tregs. NF-κB can be activated by exposure to inflammatory cytokines such as tumor necrosis factor (TNF) or IL-1, which are produced in response to bacterial and viral infections. Notch signaling activates NF-κB, interferon-γ secretion, and cell proliferation in murine Tregs [19]. In addition, NICD directly interacts with p50/c-Rel, components of the NF-κB family, in the nucleus to activate NF-κB signaling [20].

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Acknowledgements

This study was supported by KAKENHI Grant Numbers 18H02582 and 20H03394 from the Japan Society for the Promotion of Science, “Innovation Inspired by Nature” Research Support Program, Sekisui Chemical Co., Ltd., the Sumitomo Foundation, Terumo Life Science Foundation, Takahashi Industrial and Economic Research Foundation, Strategic Priority Research Promotion Program, Chiba University, “Phytochemical Plant Molecular Sciences”, and JSPS A3 Foresight Program. This work was partly supported by the National BioResource Project, Japan, (http://www.nbrp.jp/).

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  1. Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa, 223-8522, Japan

    Midori A. Arai

  2. Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan

    Itsuki Ebihara, Yoshinori Makita, Yasumasa Hara & Masami Ishibashi

  3. Medical Mycology Research Center, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8673, Japan

    Takashi Yaguchi

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Arai, M.A., Ebihara, I., Makita, Y. et al. Isolation of nocobactin NAs as Notch signal inhibitors from Nocardia farcinica, a possibility of invasive evolution. J Antibiot 74, 255–259 (2021). https://doi.org/10.1038/s41429-020-00393-z

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