Cyclooctatin, a diterpene characterized by a 5-8-5 fused ring system, is a potent inhibitor of lysophospholipase. Here we report the cloning and characterization of a complete cyclooctatin biosynthetic gene cluster from Streptomyces melanosporofaciens MI614-43F2 and heterologous production of cyclooctatin in S. albus. Sequence analysis coupled with subcloning and gene deletion revealed that the minimal cyclooctatin biosynthetic gene cluster consists of four genes, cotB1 to cotB4, encoding geranylgeranyl diphosphate (GGDP) synthase, terpene cyclase (CotB2), and two cytochromes P450, respectively. Incubation of the recombinant CotB2 with GGDP resulted in the formation of cyclooctat-9-en-7-ol, an unprecedented tricyclic diterpene alcohol. The present study establishes the complete biosynthetic pathway of cyclooctatin and provides insights into both the stereospecific diterpene cyclization mechanism of the GGDP cyclase and the molecular bases for the stereospecific and regiospecific hydroxylation.
Compounds that inactivate lipopolysaccharide (LPS) activity have the potential of being new antiinflammatory agents. Therefore, we searched among microbial secondary metabolites for compounds that inhibited LPS-stimulated adhesion between human umbilical vein endothelial cells (HUVEC) and HL-60 cells. By this screening, we found a cyclic lipopeptide surfactin from the culture broth of Bacillus sp. BML752-121F2 to be inhibitory. The addition of the surfactin prior to the LPS stimulation decreased HL-60 cell-HUVEC adhesion without showing any cytotoxicity. We confirmed that surfactin inhibited LPS-induced expression of ICAM-1 and VCAM-1 in HUVEC. It also inhibited the cellular adhesion induced by lipid A, the active component of LPS; but it did not inhibit TNF-a or IL-1b -induced cell adhesion. Then, surfactin was shown to suppress the interaction of lipid A with LPS-binding protein (LBP) that mediates the transport of LPS to its receptors. Finally, surface plasmon resonance (SPR) analysis revealed the surfactin to interact reversibly with lipid A. Thus, this Bacillus surfactin was shown to be an inhibitor of LPS-induced signal transduction, directly interacting with LPS.
Background: Because CPZEN-45 is a promising antituberculous drug candidate, the identification of the target is required. Results: CPZEN-45 inhibits the decaprenyl-phosphate-GlcNAc-1-phosphate transferase of Mycobacterium tuberculosis and the corresponding enzyme of Bacillus subtilis responsible for initiation of cell wall synthesis. Conclusion: CPZEN-45 inhibits a novel target in cell wall assembly. Significance: This study is critical for launching CPZEN-45 and for exploitation toward new antituberculous drugs.
Novel antibiotics, active against acid-fast bacteria, caprazamycins, were isolated from the culture broth of Streptomyces sp. MK730-62F2. The planar structures of the compounds were determined by 2D NMR spectroscopic study. Furthermore, the absolute structure of caprazamycin B (2) was established by NMR spectroscopy and X-ray crystallography of its degradation products and by total synthesis of the 5-amino-5-deoxy-D-ribose moiety. In the course of degradation studies of 2 under alkaline and acidic conditions, we obtained the two core components, caprazene (11) and caprazol (14), respectively, in high yield.Structurally, caprazamycins belong to a family of lipouridyl antibiotics, which have been discovered as specific inhibitors of a bacterial translocase.
Terpene cyclization reactions are fascinating owing to the precise control of connectivity and stereochemistry during the catalytic process. Cyclooctat-9-en-7-ol synthase (CotB2) synthesizes an unusual 5-8-5 fused-ring structure with six chiral centers from the universal diterpene precursor, the achiral C20 geranylgeranyl diphosphate substrate. An unusual new mechanism for the exquisite CotB2-catalyzed cyclization that involves a carbon-carbon backbone rearrangement and three long-range hydride shifts is proposed, based on a powerful combination of in vivo studies using uniformly (13)C-labeled glucose and in vitro reactions of regiospecifically deuterium-substituted geranylgeranyl diphosphate substrates. This study shows that CotB2 elegantly demonstrates the synthetic virtuosity and stereochemical control that evolution has conferred on terpene synthases.
Aminoglycoside antibiotics (AGAs) were developed at the dawn of the antibiotics era and have significantly aided in the treatment of infectious diseases. Aminoglycosides have become one of the four major types of antibiotics in use today and, fortunately, still have an important role in the clinical treatment of severe bacterial infections. In this review, the current usage, modes of action and side effects of AGAs, along with the most common bacterial resistance mechanisms, are outlined. Finally, the recent development situation and possibility of new AGAs in the 'post-antibiotic era' are considered.The Journal of Antibiotics advance online publication, 25 October 2017; doi:10.1038/ja.2017.117.
Anti-apoptotic oncoproteins Bcl-2 and Bcl-xL are overexpressed in many cancers, 1 resulting in the expansion of a transformed population and the advancement of the multidrug-resistant stage. Consequently, Bcl-2/Bcl-xL have stood out among molecular targets in oncology, and the functional blockade of these proteins will be an aid to novel anti-tumor therapies. Since these proteins are known to show an anti-apoptotic effect partly through forming a heterodimer with pro-apoptotic Bcl-2 members, such as Bax and Bak, 2 several researchers have rationally designed and synthesized compounds that target their binding pocket and have reported several compounds such as HA14-1 and ABT-737 as Bcl-2/BclxL inhibitors. 3 Currently, several lines of evidence indicate that Bcl-2/Bcl-xL clearly have other functions related to their abilities to interact physically with many other proteins; however, the underlying mechanisms for the regulation of apoptosis by Bcl-2/ Bcl-xL through interacting with such proteins still remain unclear. 4 For further understanding of the regulation of apoptosis by Bcl-2/ Bcl-xL, the development of a new class of chemical tools is required. Cell-based chemical-genetic screens have been used to help discover small, cell-permeable bioactive molecules that induce phenotypic changes, and through subsequent identification of their target proteins, they can contribute to reveal the molecular basis of biological processes. Therefore, we constructed a cell-based chemical-genetic screening system to discover small molecules that induce apoptosis in Bcl-xL-overexpressing human small cell lung carcinoma Ms-1 cells when combined with anti-tumor drugs. In the course of our screening, we isolated a structurally and functionally unique compound, named incednine (1), from the culture broth of Streptomyces sp. ML694-90F3. Here, we describe the isolation, structure elucidation, and biological activities of 1.Incednine (1) was obtained (18.9 mg/L) as a pale-yellow powder from the cultured broth of the producing strain by centrifugal liquid-liquid partition chromatography for two reasons: (1) this compound decomposes easily under acidic conditions or when exposed to light, and (2) the isolation using a solid carrier such as silica gel was inefficient. The molecular formula of 1 was found to be C 42 H 63 N 3 O 8 by HRESIMS. The characteristic UV absorption (λ max ) 294.5, 309.5, 322.5, 356.0 nm) was indicative a polyene moiety. The positive color reaction to GL reagent, negative reaction to ninhydrin, and the typical IR absorption at 1650, 1510 cm -1 suggested the presence of an amido group.The assignable NMR spectra were obtained when the sample was dissolved in CD 3 OH/H 2 O (3:1) and measured at -5°C. The 13 C NMR and DEPT spectra revealed that 1 contained 42 carbons, including one carbonyl, four quaternary sp 2 , one quaternary sp 3 , fourteen sp 2 methines, nine sp 3 methines, four methylenes, and nine methyl carbons. One carbonyl signal and eighteen sp 2 carbons require the presence of three rings from the unsaturatio...
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