The emergence of antibiotic resistance has prompted active research in the development of antibiotics with new modes of action. Among all essential bacterial proteins, transglycosylase polymerizes lipid II into peptidoglycan and is one of the most favorable targets because of its vital role in peptidoglycan synthesis. Described in this study is a practical enzymatic method for the synthesis of lipid II, coupled with cofactor regeneration, to give the product in a 50-70% yield. This development depends on two key steps: the overexpression of MraY for the synthesis of lipid I and the use of undecaprenol kinase for the preparation of polyprenol phosphates. This method was further applied to the synthesis of lipid II analogues. It was found that MraY and undecaprenol kinase can accept a wide range of lipids containing various lengths and configurations. The activity of lipid II analogues for bacterial transglycolase was also evaluated.
Four previously unreported chemical entities, boydone A (1), boydone B (2), botryorhodine F (3), and botryorhodine G (4), along with five known compounds, fusidilactone A (5), (R)-(-)-mevalonolactone (6), (R)-(-)-lactic acid (7), ovalicin (8), and botryorhodine C (9), were isolated from the ethyl acetate extracts of the fermented broths of the fungal strain Pseudallescheria boydii NTOU2362. The structures of 1-9 were characterized on the basis of their spectroscopic data analyses. The absolute configurations of 1 and 2 were established by comparison with the literature and the modified Mosher's method. The growth inhibitory activities of 1-9 against the A549 non-small-cell lung cancer cell line were evaluated, and 2 and 8 exhibited moderate to potent bioactivities with GI₅₀ values of 41.3 and 4.1 μM, respectively, in comparison with fluorouracil (GI₅₀ = 3.6 μM).
Four new tetracyclic diterpene glycosides, namely, sordarins C-F (1-4), and three new γ-lactone polyketides, namely, xylogiblactones A-C (5-7), along with sordarin were isolated from the ethyl acetate extracts of the fermented broths of Xylotumulus gibbisporus YMJ863. The structures of 1-7 were elucidated on the basis of spectroscopic data analyses. The configurations of 1-4 were deduced by NOESY, molecular modeling, and comparison with the literature. The relative configurations of 5-7 were deduced by X-ray crystallographic analysis of 5. Compounds 1-5 and sordarin were evaluated in an antifungal assay using Candida albicans ATCC 18804, C. albicans ATCC MYA-2876, and Saccharomyces cerevisiae ATCC 2345, and only sordarin exhibited significant antifungal activities against these fungal strains, with MIC values of 64.0, 32.0, and 32.0 μg/mL, respectively. The effect of compounds 1-7 and sordarin on the inhibition of NO production in lipopolysaccharide-activated murine macrophages was also evaluated. Compounds 2 and sordarin inhibited NO production with IC50 values of 327.2±46.6 and 157.1±24.1 μM, respectively.
The emergence of antibiotic resistance has prompted active research in the development of antibiotics with new modes of action. Among all essential bacterial proteins, transglycosylase polymerizes lipid II into peptidoglycan and is one of the most favorable targets because of its vital role in peptidoglycan synthesis. Described in this study is a practical enzymatic method for the synthesis of lipid II, coupled with cofactor regeneration, to give the product in a 50–70 % yield. This development depends on two key steps: the overexpression of MraY for the synthesis of lipid I and the use of undecaprenol kinase for the preparation of polyprenol phosphates. This method was further applied to the synthesis of lipid II analogues. It was found that MraY and undecaprenol kinase can accept a wide range of lipids containing various lengths and configurations. The activity of lipid II analogues for bacterial transglycolase was also evaluated.
Five novel sesquiterpene glycosides, namely, cosmosporasides A-E (1-5), were isolated from the ethyl acetate extract of the fermented broth of Cosmospora joca. The structures of 1-5 were elucidated on the basis of spectroscopic data analyses, monosaccharide composition analyses, and monosaccharide chirality analyses. The relative configuration of the sesquiterpene moiety of 3-5 was determined by J-based configuration analyses and supported by NOESY assignments. The inhibitory effects of 1-5 on the nitric oxide (NO) production in lipopolysaccharide (LPS)-activated murine macrophage RAW264.7 cells were evaluated; all except 3 inhibited NO production at 100 μM. 4 was the most potent, with an average maximum inhibition and a median inhibitory concentration value of 71.70 ± 1.23% and 65.98 ± 0.53 μM, respectively.
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