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Pleuromutilins, the unique fungal metabolites possessing 5/6/8 tricyclic skeleton, are potent antibacterial leading compounds for the development of new antibiotics. We applied the MS/MS molecular networking technique and the combinatorial biosynthesis approach to discover new pleuromutilin analogues. Ten pleuromutilin derivatives including seven new compounds (1-7) were obtained from the solid culture of Omphalina mutila. The gene cluster for the biosynthesis of pleuromutilins in the mushroom of O. mutila was identified and further expressed in yeast. Nine pleuromutilin-type diterpenes including three new "unnatural" pleuromutilins (16-18) were generated in a GGPP-engineered Saccharomyces cerevisiae. The antimicrobial bioassays indicated that compounds 3, 9, 10, 15, and 17 exhibited potent inhibition against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE). Several pleuromutilins were found to show immunomodulatory activities by promoting the cell viability, enhancing the ROS and NO production, or increasing the levels of proinflammatory cytokines IL-6 and TNF-α in the macrophage RAW 264.7. The structure-activity relationship for pleuromutilins was analyzed.

Polysaccharides are known to confer protection against obesity via modulation of gut microbiota. To expand our knowledge of mushroom-derived prebiotics, we investigated the structural characteristics and anti-obesity effects of Lyophyllum decastes polysaccharides. Two heteroglycans were purified and characterized. The isolated polysaccharides effectively reduced obesity and the related disorders in the diet-induced obese (DIO) mice. An altered gut microbiota with enrichments of Bacteroides intestinalis and Lactobacillus johnsonii and an increase of secondary bile acids were detected in the polysaccharide-treated mice. Supplementation of B. intestinalis and L. johnsonii prevented the obesity and hyperlipidemia in DIO mice, demonstrating their causal linkage to the efficacy of polysaccharides. An enhancement of energy expenditure in the brown adipose tissues due to up-regulation of the secondary bile acids-activated TGR5 pathway was deduced to be one of the mechanisms underlying the effect of polysaccharides. These results confirmed Lyophyllum decastes-derived polysaccharides as new prebiotics for preventing and treating obesity.

As an anti-tuberculosis target, DprE1 contains two flexible loops (Loop I and Loop II) which have never been exploited for developing DprE1 inhibitors. Here Leu317 in Loop II was discovered as a new functional site to combat drug-resistance in Mycobacterium strains. Based on TCA1, LZDT1 was designed to optimize the hydrophobic interaction with Leu317. A subsequent biochemical and cellular assay displayed increased potency of LZDT1 in inhibiting DprE1 and killing drug-sensitive/-resistant Mycobacterium strains. The improved activity of LZDT1 and its analogue LZDT2 against multidrug resistant tuberculosis was particularly highlighted. For LZDT1, its enhanced interaction with Leu317 also impaired the drug-insensitivity of DprE1 caused by Cys387 mutation. A new nonbenzothiazole lead (LZDT10) with reduced Cys387-dependence was further produced by optimizing interactions with Leu317, improvement directions for LZDT10 were discussed as well. Our research underscores the value of potential functional sites in disordered loops, and affords a feasible way to develop these functional sites into opportunities for drug-resistance management.

Two potent anti-MRSA tanshinone glycosides (1 and 2) were discovered by targeted microbial biotransformation, along with rapid identification via MS/MS networking. Serial reactions including dehydrogenation, demethylations, reduction, glycosylation and methylation have been observed after incubation of tanshinone IIA and fungus Mucor rouxianus AS 3.3447. In addition, tanshinosides B (2) showed potent activities against serial clinical isolates of oxacillin-resistant Staphylococcus aureus with MIC values of 0.78 μg/mL. This is the first study that shows a significant increase in the level and activities of tanshinone glycosides relative to the substrate tanshinone IIA.

Three new cardenolides (3, 9 and 10), along with eight known ones, were isolated from the latex of Calotropis procera. The structural determination was accomplished by the 1D- and 2D-NMR spectra as well as HRESIMS analysis. The growth inhibitory activity of the latex and its sub-fractions as well as isolated compounds was evaluated against human A549 and Hela cell lines. The results exhibited that latex had strong growth inhibitory activity with IC50s of (3.37 μM, A-549) and (6.45 μM, Hela). Among the four extracts (hexane, chloroform, ethyl acetate and aqueous), chloroform extract displayed the highest potential cytotoxic activity, with IC50s of (0.985 μM, A-549) and (1.471 μM, Hela). All the isolated compounds displayed various degrees of cytotoxic activity and the highest activity was observed by calactin (1) with IC50s values of (0.036 μM, A-549) and (0.083 μM, Hela). None of these isolated compounds exhibited good antimicrobial activity evaluated by determination of their MICs using the broth microdilution method against various infectious pathogens. The structure-activity relationships for cytotoxic activity were also discussed.

Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) have caused an increasing mortality rate, which means that antibiotic resistance is becoming an important health issue. In the course to screen new agents for resistant bacteria, we identified that a series of isatin-β-thiosemicarbazones (IBTs) could inhibit the growth of MRSA and VRE. This was the first time that the “familiar” IBT compounds exhibited significant anti Gram-positive pathogen activity. Against a clinical isolated MRSA strain, 20 of the 51 synthesized compounds showed minimum inhibitory concentration (MIC) data of 0.78 mg/L and another 12 novel compounds had MICs of 0.39 mg/L. Moreover, these compounds also inhibited Enterococcus faecalis and VRE at similar levels, indicating that IBTs might have different mode of action compared with vancomycin. For these IBTs, comparative field analysis (CoMFA) models were further established to understand the structure–activity relationships in order to design new compounds from steric and electrostatic contributions. This work has suggested that IBTs can be considered as potential lead compounds to discover antibacterial inhibitors to combat drug resistance.

A total of 29 novel sulfenamide compounds were synthesized, spectroscopically characterized and evaluated in vitro for antimicrobial activity against various infectious pathogens. Compounds 1b and 2c exhibited potent inhibition against clinical Methicillin-resistant Staphylococcus aureus (MRSA) strains with minimum inhibitory concentration (MIC) values of 1.56 μg/mL.

A new oxysporidinone analogue (1) and a new 3-hydroxyl-2-piperidinone derivative (2), along with the known compounds (-)-4,6'-anhydrooxysporidinone (3), (+)-fusarinolic acid (4), gibepyrone D (5), beauvercin (6),cerevisterol (7), fusaruside (8), and (2S,2'R,3R,3'E,4E,8E)-1-O-D-glucopyranosyl-2-N-(2'-hydroxy-3'-octadecenoyl)-3-hydroxy-9-methyl-4,8-sphingadienine (9) were isolated from Fusarium oxysporum. Compounds 1-9 were evaluated for cytotoxicity using the MTT method against cancer cell lines, PC-3, PANC-1, and A549. Beauvericin showed cytotoxicity against PC-3, PANC-1, and A549 with IC(50) value of 49.5 ± 3.8, 47.2 ± 2.9, and 10.4 ± 1.6μM, respectively. Beauvericin also exhibited anti-bacterial activity towards methicillin-resistant Staphylococcus aureus (MIC=3.125 μg/mL) and Bacillus subtilis (MIC=3.125 μg/mL).

Two new naphthalene acylglucosides, rumexneposides A (1) and B (2), together with 12 known compounds (3-14), were isolated from the roots of Rumex nepalensis. Their structures were established by chemical and spectroscopic methods. The biological activities of compounds 1-14 as well as an additional 11 compounds previously isolated from R. nepalensis and Rumex hastatus (15-25) were evaluated against Mycobacterium tuberculosis, para-aminobenzoic acid (pAba) pathway, and a panel of human cancer cell lines. The results showed that compound 15 was the most active against M. tuberculosis with an MIC value of 2.85 mu M similar to that of isoniazid. Compound 5 could inhibit pAba synthetic pathway with an MIC value of 12.6 mu M, comparable to that of positive control abyssomicin C, representing a new example of the rare pAba pathway inhibitors. (C) 2010 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.

SummaryAnsamitocins are potent antitumor maytansinoids produced by Actinosynnema pretiosum. Their biosynthesis involves the initial assembly of a macrolactam polyketide, followed by a series of postpolyketide synthase (PKS) modifications. Three ansamitocin glycosides were isolated from A. pretiosum and fully characterized structurally as novel ansamitocin derivatives, carrying a β-D-glucosyl group attached to the macrolactam amide nitrogen in place of the N-methyl group. By gene inactivation and complementation, asm25 was identified as the N-glycosyltransferase gene responsible for the macrolactam amide N-glycosylation of ansamitocins. Soluble, enzymatically active Asm25 protein was obtained from asm25-expressing E. coli by solubilization from inclusion bodies. Its optimal reaction conditions, including temperature, pH, metal ion requirement, and Km/Kcat, were determined. Asm25 also showed broad substrate specificity toward other ansamycins and synthetic indolin-2-ones. To the best of our knowledge, this represents the first in vitro characterization of a purified antibiotic N-glycosyltransferase.

La 2 Zr 2 O 7 (LZ) is a promising thermal barrier coating material for the high-temperature applications, which could be significantly toughened by the YAG nanopowder incorporated into the matrix. The composites of x YAG/(1 − x )LZ ( x = 10, 15, 20 vol.%, LZ- x -YAG) were densified by means of high-pressure sintering (HPS) under a pressure of 4.5 GPa at 1650 °C for 5 min, by which a high-relative density above 93% could be obtained. The morphologies of the fractured surfaces were investigated by the scanning electron microscope, and the fracture toughness and Vicker's-hardness of the composites were evaluated by the microindentation. The grain size of the LZ matrix drops significantly with the addition of YAG nanoparticles and the fracture type changes from the intergranular to a mixture type of the transgranular and intergranular in the nanocomposites. The LZ-20-YAG nanocomposite has a fracture toughness of 1.93 MPa m 1/2 , which is obviously higher than that of the pure LZ (1.57 MPa m 1/2 ), and the toughening mechanism is discussed in this paper.

Chemical analysis of an East China Sea marine-derived fungus, Aspergillus sydowii (MF357) returned three new tris-pyrogallol ethers, sydowiols A-C (1-3), and two known bis-pyrogallol ethers, violaceols I (4) and 11 (5). Structures were assigned on the basis of detailed spectroscopic analysis and by consideration of symmetry. Sydowiols A (1) and C (3) were responsible for the inhibitory activity detected in the crude fungal extract against Mycobacterium tuberculosis protein tyrosine phosphatase A (PtpA). (C) 2013 Elsevier Ltd. All rights reserved.

Herein, we describe the isolation of rare alkaloids, haenamindole and citreoindole, from a South China Sea deep-sea fungus, Penicillium citrinum (MF006), and their structure revision based on detailed spectroscopic and C3 Marfey’s analysis.

In this study, we report three novel naturally occurring compounds, blapsins A (1) and B (2), and blapsamide (3) from the ethanol extract of the stink beetle, Blaps japanensis. The structures of these compounds were determined using spectroscopic methods. Compound 3 is a phenolic compound bearing a formamido group in the structure. Functional studies revealed that compounds 1 and 2 potently inhibited 14-3-3 protein-protein interactions (PPIs) with IC50 values of 9.2 and 10.0 mu M as determined by an ELISA assay, and 2.0 and 2.5 mu M in an FP assay, respectively. These compounds represent the first example of natural small-molecule 14-3-3 inhibitors. (C) 2012 Elsevier Ltd. All rights reserved.

A new triterpenoid, cucubalugenin A (1), has been isolated from the whole plant of Cucubalus baccifer. Its structure was elucidated by spectral methods.