9-Methylstreptimidone

We previously reported that 9-methylstreptimidone, a piperidine compound isolated from a culture filtrate of Streptomyces, induces apoptosis selectively in adult T-cell leukemia cells. It was screened for a compound that inhibits LPS-induced NF-kappaB and NO production in mouse macrophages. However, 9-methystreptimidone is poorly obtained from the producing microorganism and difficult to synthesize. Therefore, in the present research, we studied the structure-activity relationship to look for new selective inhibitors. We found that the structure of the unsaturated hydrophobic portion of 9-methylstreptimidone was essential for the inhibition of LPS-induced NO production. Among the 9-methylstreptimidone-related compounds tested, (+/-)-4,alpha-diepi-streptovitacin A inhibited NO production in macrophage-like cells as potently as 9-methylstreptimidone and without cellular toxicity. Moreover, this compound selectively induced apoptosis in adult T-cell leukemia MT-1 cells.

We have isolated 9-methylstreptimidone from microorganism as a new NF-κB inhibitor. Later, we designed 3-[(dodecylthiocarbonyl) methyl]-glutarimide (DTCM-glutarimide) as an analog of this compound, which shows anti-inflammatory activity in vivo. In the present research, we found that DTCM-glutarimide inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation of mouse bone marrow-derived macrophages and RANKL- or lipopolysaccharide (LPS)-induced osteoclast differentiation of RAW 264.7 cells without any toxicity. It also inhibited the RANKL-induced NFATc1 expression. Upstream signaling involving phosphorylation of Akt and GSK-3β was induced by RANKL, of which the signaling was inhibited by DTCM-glutarimide. Then DTCM-glutarimide was confirmed to inhibit RANKL-induced NF-κB activity, possibly by inhibiting the Akt-mediated activation of IKK. Thus, DTCM-glutarimide inhibited osteoclastogenesis by blocking both the Akt-GSK3β-NFATc1 and NF-κB-NFATc1 pathways. DTCM-glutarimide may be a candidate as a chemotherapeutic agent for severe bone resorption diseases.

The fungal pathogenBotrytis cinereais the causal agent of devastating gray mold diseases in many economically important fruits, vegetables, and flowers, leading to serious economic losses worldwide. In this study, a novel actinomycete NEAU-LD23Texhibiting antifungal activity againstB. cinereawas isolated, and its taxonomic position was evaluated using a polyphasic approach. Based on the genotypic, phenotypic and chemotaxonomic data, it is concluded that the strain represents a novel species within the genusStreptomyces, for which the nameStreptomyces botrytidirepellenssp. nov. is proposed. The type strain is NEAU-LD23T(=CCTCC AA 2019029T=DSM 109824T). In addition, strain NEAU-LD23Tshowed a strong antagonistic effect againstB. cinerea(82.6±2.5%) and varying degrees of inhibition on nine other phytopathogenic fungi. Both cell-free filtrate and methanol extract of mycelia of strain NEAU-LD23Tsignificantly inhibited mycelial growth ofB. cinerea. To preliminarily explore the antifungal mechanisms, the genome of strain NEAU-LD23Twas sequenced and analyzed. AntiSMASH analysis led to the identification of several gene clusters responsible for the biosynthesis of bioactive secondary metabolites with antifungal activity, including 9-methylstreptimidone, echosides, anisomycin, coelichelin and desferrioxamine B. Overall, this research provided us an excellent strain with considerable potential to use for biological control of tomato gray mold.