Biology DivisionLaboratory of Microbiology
Osada Unit

Themes

1. Phenotypic screening for new antifungal agents
2. Target identification of novel antibiotics
3. in vivo Antifungal activity test using silkworms as a model organism

Theme outlines

1. Phenotypic screening for new antifungal agents

We carry out in-house phenotypic evaluation (iHOPE) screening system, where the growth inhibitory activity of test samples against not only fungi, but also mammalian cells, bacteria, and protozoa are systematically evaluated. By profiling characteristic growth inhibition patterns, called “Fingerprints”, highly specific antifungals can be selected. We have also constructed other phenotypic screening system using MorphoBase, a database of cell morphological changes induced by typical antifungal drugs, and use MorphoBase to screen promising first-in-class compounds from initial hits. Currently, we are improving the system by introducing AI that has learned a huge amount of image data to accelerate our drug discovery program.

2. Target identification of novel antibiotics

The Merck Candida albicans double barcoded strain library (DBC) is a collection of haploid mutants in ca. 5,000 distinct genes. Haploinsufficiency is a phenomenon where the drug sensitivity increases when the amount of the target protein is reduced. The genome-wide haploinsufficiency profiling using this collection enabled to speculate the mode of action of various antifungal agents (PLoS Pathog, 2007). We are analyzing the mode of action of screening hits by this genetic interaction-based approach as well as other physiological interaction-based ones, such as affinity selection by compound-immobilized beads and cell thermal shift assay.

3. in vivo Antifungal activity test using silkworms as a model organism

Compared to mice as a model organism, silkworms have many advantages, such as easy to handle, low cost, and few ethical issues. Recently, in vivo models using silkworms infected with various pathogenic microbes were reported and utilized for the evaluation of therapeutic potential of antibiotics (Microbe Pathog, 2002). We applied this system and are evaluating in vivo antifungal activity of the antifungal candidates.

Publications

BIL7 enhances plant growth by regulating the transcription factor BIL1/BZR1 during brassinosteroid signaling.
T. Miyaji, A. Yamagami, Y. Nakamura, K. Nishida, R. Tachibana, S. Surina, S. Fujioka, M. Garcia-Hourquet, S. Mora-García, S. Nosaki, T. Miyakawa, M. Tanokura, M. Matsui, H. Osada, K. Shinozaki, T. Asami, and T. Nakano.
Plant J, 2024, doi: 10.1111/tpj.17212

Synergistic involvement of the NZF domains of the LUBAC accessory subunits HOIL-1L and SHARPIN in the regulation of LUBAC function.
Y. Toda, H. Fujita, K. Mino, T. Koyama, S. Matsuoka, T. Kaizuka, M. Agawa, S. Matsumoto, A. Idei, M. Nishikori, Y. Okuno, H. Osada, M. Yoshida, A. Takaori-Kondo, and K. Iwai.
Cell Death Dis, 2024, 15, 813, doi: 10.1038/s41419-024-07199-z

Reprogramming of flagellin receptor responses with surrogate ligands.
D. H. Lee, H. S. Lee, M. S. Choi, K. Parys, K. Honda, Y. Kondoh, J. M. Lee, N. Edelbacher, G. Heo, B. Enugutti, H. Osada, K. Shirasu, and Y. Belkhadir.
Nat Commun, 2024, 15, 9811, doi: 10.1038/s41467-024-54271-5

Total synthesis, stereochemical assignment, and biological evaluation of opantimycin A and analogues thereof.
Y. Usuki, R. Abe, K. Nishiguchi, T. Satoh, H. Aono, T. Nogawa, Y. Futamura, H. Osada, I. Yoshida, K. Fujita, T. Mishima, and K. I. Fujita.
Org Biomol Chem, 2024, 22, 8973-8979, doi: 10.1039/d4ob01475h

Modulation of fungal phosphate homeostasis by the plant hormone strigolactone.
J. M. Bradley, M. Bunsick, G. Ly, B. Aquino, F. Z. Wang, D. Holbrook-Smith, S. Suginoo, D. Bradizza, N. Kato, O. As'sadiq, N. Marsh, H. Osada, F. D. Boyer, C. S. P. McErlean, Y. Tsuchiya, R. Subramaniam, D. Bonetta, P. McCourt, and S. Lumba.
Mol Cell, 2024, 84, 4031-4047, doi: 10.1016/j.molcel.2024.09.004

Pyricularia oryzae enhances Streptomyces griseus growth via non-volatile alkaline metabolites.
R. Sugiura, T. Arazoe, T. Motoyama, H. Osada, T. Kamakura, K. Kuramochi, and Y. Furuyama.
Environ Microbiol Rep, 2024, 16, e70012, doi: 10.1111/1758-2229.70012

Porphyrin derivatives inhibit tumor necrosis factor α-induced gene expression and reduce the expression and increase the cross-linked forms of cellular components of the nuclear factor κB signaling pathway.
Q. V. Vu, N. T. Vu, K. Baba, S. Sasaki, R. Tamura, K. Morimoto, H. Hirano, H. Osada, and T. Kataoka.
Eur J Pharmacol, 2024, 977, 176747, doi: 10.1016/j.ejphar.2024.176747

Structural and functional analyses of inhibition of human dihydroorotate dehydrogenase by antiviral furocoumavirin.
M. Nakahara, S. Watanabe, M. Sato, H. Okumura, M. Kawatani, H. Osada, K. Hara, H. Hashimoto, and K. Watanabe.
Biochemistry, 2024, 63, 1241-1245, doi: 10.1021/acs.biochem.4c00120

Identification of a family of species-selective complex I inhibitors as potential anthelmintics.
T. Davie, X. Serrat, L. Imhof, J. Snider, I. Štagljar, J. Keiser, H. Hirano, N. Watanabe, H. Osada, and A. D. Fraser.
Nat Commun, 2024, 15, 3367, doi: 10.1038/s41467-024-47331-3

Expression of Syo_1.56 SARP regulator unveils potent elasnin derivatives with antibacterial activity.
I. A. Abdelhakim, Y. Futamura, Y. Asami, H. Hanaki, N. Kito, S. Masuda, A. Shibata, A. Muranaka, H. Koshino, K. Shirasu, H. Osada, J. Ishikawa, and S. Takahashi.
J Nat Prod, 2024, 87, 1459-1470, doi: 10.1021/acs.jnatprod.4c00259

Reclassification of a reveromycin-producer and the proposals of Actinacidiphila reveromycinica sp. nov. and Actinacidiphila acidipaludis comb. nov.
H. Komaki, H. Takagi, S. Takahashi, and H. Osada.
Biosci Biotechnol Biochem, 2024, 88, 689-695, doi: 10.1093/bbb/zbae032

Production of kinanthraquinone D with antimalarial activity by heterologous gene expression and biotransformation in Streptomyces lividans TK23.
K. Sakai, Y. Futamura, T. Nogawa, Y. Zhao, H. Koshino, H. Osada, and S. Takahashi.
J Nat Prod, 2024, 87, 855-860, doi: 10.1021/acs.jnatprod.3c01076

Amiodarone inhibits the Toll-like receptor 3-mediated nuclear factor κB signaling pathway by blocking organelle acidification.
Y. Yokota, K. Takaki, K. Baba, S. Sasaki, H. Hirano, H. Osada, and T. Kataoka.
Biochem Biophys Res Commun, 2004, 708, 149801, doi: 10.1016/j.bbrc.2024.149801

Alantolactone derivatives inhibit the tumor necrosis factor α-induced nuclear factor κB pathway by a different mechanism from alantolactone.
Q. V. Vu, K. Baba, S. Sasaki, K. Kawaguchi, H. Hirano, H. Osada H, and T. Kataoka.
Eur J Pharmacol, 2024, 969, 176458, doi: 10.1016/j.ejphar.2024.176458