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.
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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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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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