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



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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  1. Mogensen TH. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev. 2009;22:240–73.

    Article  CAS  Google Scholar 

  2. Dziarski R. Recognition of bacterial peptidoglycan by the innate immune system. Cell Mol Life Sci. 2003;60:1793–804.

    Article  CAS  Google Scholar 

  3. Brown-Elliott BA, Brown JM, Conville PS, Wallace RJ Jr. Clinical and laboratory features of the Nocardia spp. based on current molecular taxonomy. Clin Microbiol Rev. 2006;19:259–82.

    Article  CAS  Google Scholar 

  4. Eisenblätter M, Disko U, Stoltenburg-Didinger G, Scherübl H, Schaal KP, Roth A, et al. Isolation of Nocardia paucivorans from the cerebrospinal fluid of a patient with relapse of cerebral nocardiosis. J Clin Microbiol. 2002;40:3532–4.

    Article  Google Scholar 

  5. Hara Y, Arai MA, Sakai K, Ishikawa N, Gonoi T, Yaguchi T, et al. Dehydropropylpantothenamide isolated by a co-culture of Nocardia tenerifensis IFM 10554T in the presence of animal cells. J Nat Med. 2018;72:280–9.

    Article  CAS  Google Scholar 

  6. Hara Y, Arai MA, Toume K, Masu H, Sato T, Komatsu K, et al. Coculture of a pathogenic actinomycete and animal cells to produce nocarjamide, a cyclic nonapeptide with Wnt signal-activating effect. Org Lett. 2018;20:5831–4.

    Article  CAS  Google Scholar 

  7. Schaale K, Neumann J, Schneider D, Ehlers S, Reiling N. Wnt signaling in macrophages: augmenting and inhibiting mycobacteria-induced inflammatory responses. Eur J Cell Biol. 2011;90:553–9.

    Article  CAS  Google Scholar 

  8. Andersson ER, Sandberg R, Lendahl U. Notch signaling: simplicity in design, versatility in function. Development. 2011;138:3593–612.

    Article  CAS  Google Scholar 

  9. Borggrefe T, Oswald F. The Notch signaling pathway: transcriptional regulation at Notch target genes. Cell Mol Life Sci. 2009;66:1631–46.

    Article  CAS  Google Scholar 

  10. Chitnis A, Bally-Cuif L. The Notch meeting: an odyssey from structure to function. Development. 2016;143:547–53.

    Article  CAS  Google Scholar 

  11. Kovall RA, Gebelein B, Sprinzak D, Kopan R. The canonical Notch signaling pathway: structural and biochemical insights into shape, sugar, and force. Dev Cell. 2017;41:228–41.

    Article  CAS  Google Scholar 

  12. Amsen D, Helbig C, Backer RA. Notch in T cell differentiation: all things considered. Trends Immunol. 2015;36:802–14.

    Article  CAS  Google Scholar 

  13. Radtke F, MacDonald HR, Tacchini-Cottier F. Regulation of innate and adaptive immunity by Notch. Nat Rev Immunol. 2013;13:427–37.

    Article  CAS  Google Scholar 

  14. Maekawa Y, Tsukumo S, Chiba S, Hirai H, Hayashi Y, Okada H, et al. Delta1-Notch3 interactions bias the functional differentiation of activated CD4+ T cells. Immunity 2003;19:549–59.

    Article  CAS  Google Scholar 

  15. Minter LM, Turley DM, Das P, Shin HM, Joshi I, Lawlor RG, et al. Inhibitors of gamma-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21. Nat Immunol 2005;6:680–8.

    Article  CAS  Google Scholar 

  16. Bailis W, Yashiro-Ohtani Y, Fang TC, Hatton RD, Weaver CT, Artis D, et al. Notch simultaneously orchestrates multiple helper T cell programs independently of cytokine signals. Immunity. 2003;39:148–59.

    Article  Google Scholar 

  17. Kang JH, Kim BS, Uhm TG, Lee SH, Lee GR, Park CS, et al. γ-Secretase inhibitor reduces allergic pulmonary inflammation by modulating Th1 and Th2 responses. Am J Respir Crit Care Med. 2009;179:875–82.

    Article  CAS  Google Scholar 

  18. Charbonnier LM, Wang S, Georgiev P, Sefik E, Chatila TA. Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling. Nat Immunol. 2015;16:1162–73.

    Article  CAS  Google Scholar 

  19. Palaga T, Miele L, Golde TE, Osborne BA. TCR-mediated Notch signaling regulates proliferation and IFN-γ production in peripheral T cells. J Immunol. 2003;171:3019–24.

    Article  CAS  Google Scholar 

  20. Shin HM, Minter LM, Cho OH, Gottipati S, Fauq AH, Golde TE, et al. Notch1 augments NF-κB activity by facilitating its nuclear retention. EMBO J. 2006;25:129–38.

    Article  CAS  Google Scholar 

  21. Dovey HF, et al. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem. 2001;76:173–81.

    Article  CAS  Google Scholar 

  22. Borghese L, Dolezalova D, Opitz T, Haupt S, Leinhaas A, Steinfarz B, et al. Inhibition of Notch signaling in human embryonic stem cell-derived neural stem cells delays G1/S phase transition and accelerates neuronal differentiation in vitro and in vivo. Stem Cells. 2010;28:955–64.

    Article  CAS  Google Scholar 

  23. Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, et al. Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem. 2004;279:12876–82.

    Article  CAS  Google Scholar 

  24. Luistro L, He W, Smith M, Packman K, Vilenchik M, Carvajal D, et al. Preclinical profile of a potent γ-secretase inhibitor targeting Notch signaling with In vivo efficacy and pharmacodynamic properties. Cancer Res. 2009;69:7672–80.

    Article  CAS  Google Scholar 

  25. Hoffman LM, Fouladi M, Olson J, Daryani VM, Stewart CF, Wetmore C, et al. Phase I trial of weekly MK-0752 in children with refractory central nervous system malignancies: a pediatric brain tumor consortium study. Child Nerv Syst. 2015;31:1283–9.

    Article  Google Scholar 

  26. Arcaroli JJ, Quackenbush KS, Purkey A, Powell RW, Pitts TM, Bagby S, et al. Tumours with elevated levels of the Notch and Wnt pathways exhibit efficacy to PF-03084014, a γ-secretase inhibitor, in a preclinical colorectal explant model. Br J Cancer. 2013;109:667–75.

    Article  CAS  Google Scholar 

  27. Yoneyama T, Arai MA, Akamine R, Koryudzu K, Sadhu SK, Ahmed F, et al. Notch inhibitors from Calotropis gigantea that induce neuronal differentiation of neural stem cells. J Nat Prod 2017;80:2453–61.

  28. Larsson R, Fridborg H, Kristensen J, Sundström C, Nygren P. In vitro testing of chemotherapeutic drug combinations in acute myelocytic leukaemia using the fluorometric microculture cytotoxicity assay (FMCA). Br J Cancer. 1993;67:969–74.

    Article  CAS  Google Scholar 

  29. Arai MA, Akamine R, Tsuchiya A, Yoneyama T, Koyano T, Kowithayakorn T, et al. The Notch inhibitor cowanin accelerates nicastrin degradation. Sci Rep. 2018;8:5376.

    Article  Google Scholar 

  30. Arai MA, Akamine R, Hayashi N, Koyano T, Kowithayakorn T, Ishibashi M. The Notch inhibitors isolated from Nerium indicum. J Nat Prod. 2018;81:1235–40.

    Article  CAS  Google Scholar 

  31. Tsuchiya A, Makita Y, Koyano T, Kowithayakorn T, Ishibashi M, Arai MA. Isolation and evaluation of cardenolides from Lansium domesticum as Notch inhibitors. J. Nat. Med. 2020;74:758–66.

  32. Hoshino Y, Chiba K, Ishino K, Fukui T, Igarashi Y, Yazawa K, et al. Identification of nocobactin NA biosynthetic gene clusters in Nocardia farcinica. J Basteriol. 2011;193:441–8.

    Article  CAS  Google Scholar 

  33. Weng AP, et al. Activating mutations of NOTCH1 in human cell acute lymphoblastic leukemia. Science. 2004;306:269–71.

    Article  CAS  Google Scholar 

  34. Sakagami H, Ishihara M, Hoshino Y, Ishikawa J, Mikami Y, Fukai T. Cytotoxicity of nocobactins NA-a, NA-b and their ferric complexes assessed by semiempirical molecular orbital method. In Vivo. 2005;19:277–82.

    CAS  PubMed  Google Scholar 

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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, (

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Correspondence to Midori A. Arai.

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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).

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