New cyslabdans B and C, potentiators of imipenem activity against methicillin-resistant Staphylococcus aureus produced by Streptomyces sp. K04-0144

From a further purification study,two new congeners designated cyslabdans B(1)and C(2)were isolated along with previously reported cyslabdan(cyslabdan A(3)in this study)from the culture broth of Streptomyces sp.K04-0144.The structure was elucidated by various spectroscopy including NMR,revealing that 1 and 2 was 18-hydroxy and 10-methoxy cyslabdan,respectively.Compounds 1 and 2 were found to potentiate imipenem activity against methicillinresistant Staphylococcus aureus by 123 fold and 533 fold,respectively.Comparison with the activity of compound 3 indicated that the introduction of a hydrophilic group at the dimethyl moiety of the decalin ring was unfavorable for its activity.

Beauvericin counteracted multi-drug resistant Candida albicans by blocking ABC transporters

Multi-drug resistance of pathogenic microorganisms is becoming a serious threat,particularly to immunocompromised populations.The high mortality of systematic fungal infections necessitates novel antifungal drugs and therapies.Unfortunately,with traditional drug discovery approaches,only echinocandins was approved by FDA as a new class of antifungals in the past two decades.Drug efflux is one of the major contributors to multi-drug resistance,the modulator of drug efflux pumps is considered as one of the keys to conquer multi-drug resistance.In this study,we combined structure-based virtual screening and whole-cell based mechanism study,identified a natural product,beauvericin(BEA)as a drug efflux pump modulator,which can reverse the multi-drug resistant phenotype of Candida albicans by specifically blocking the ATP-binding cassette(ABC)transporters;meantime,BEA alone has fungicidal activity in vitro by elevating intracellular calcium and reactive oxygen species(ROS).It was further demonstrated by histopathological study that BEA synergizes with a sub-therapeutic dose of ketoconazole(KTC)and could cure the murine model of disseminated candidiasis.Toxicity evaluation of BEA,including acute toxicity test,Ames test,and hERG(human ether-a-go-go-related gene)test promised that BEA can be harnessed for treatment of candidiasis,especially the candidiasis caused by ABC overexpressed multi-drug resistant C.albicans.

Discovery of new hazimycin congeners from Kitasatospora sp.P07101

In an analytical study of microbial broths,the actinomycete strain Kitasatospora sp.P07101 was found to produce three new congeners,which were designated hazimycins B(1),C(2),and D(3),together with the previously reported hazimycin(renamed hazimycin A(4)).The structures of these hazimycins were examined using various spectroscopic methods including nuclear magnetic resonance(NMR),and the results revealed that 1–3 were analogues of hazimycin with the replacement of one of the two isonitrile groups in 4 by an NH-formyl group in 1,the two isonitrile groups and an amide group by two NH-formyl groups and a nitrile group in 2,and the two isonitrile groups and two amide groups by two NH-formyl groups and two nitrile groups in 3.Only hazimycin A exhibited moderate antimicrobial activities against Gram-positive bacteria and Candida albicans.These results indicated that the presence of two isonitrile groups in the hazimycin structure is essential for antimicrobial activity.

Inhibition of tyrosinase activity and melanine pigmentation by 2-hydroxytyrosol

2-Hydroxytyrosol(2-HT),originally reported as a synthetic compound,was isolated for the first time as a fungal metabolite.2-HT was found to inhibit mushroom tyrosinase with an IC_(50) value of 13.0 mmol/L.Furthermore,2-HT dose-dependently inhibited tyrosinase activity(IC_(50),32.5 mmol/L)in the cell-free extract of B16 melanoma cells andα-melanocyte stimulating hormone(α-MSH)-stimulated melanin formation in intact B16 melanoma cells.

Stereochemistries of monapinones produced by Talaromyces pinophilus FKI-3864

Monapinones A(1)to E(5),half parts of dinapinones,were produced by fermentation of Talaromyces pinophilus FKI-3864 in seawater-containing medium and have a common dihydronaphthopyranone skeleton with a different long alkyl chain.The relative stereochemistries of 3–5 were elucidated by various NMR experiments including analysis of 1 H NMR coupling constants,ROESY and the dihedral angles.The absolute stereochemistries of 3–5 at C-3 were determined by the circular dichroism spectra in comparison to the data of(R)-and(S)-semivioxanthins(6 and 7).Accordingly,total absolute stereochemistries of 3–5 were concluded to be 3S,13R,15R,17R,19R,3S,13R,15R,17R and 3S,13R,15R,respectively.

Fungal pyrrolidine-containing metabolites inhibit alkaline phosphatase activity in bone morphogenetic protein-stimulated myoblastoma cells

Fibrodysplasia ossificans progressiva(FOP)is a rare autosomal dominant congenital disorder characterized by progressive heterotopic ossification in muscle tissues.A constitutively activated mutation of a bone morphogenetic protein(BMP)receptor,ALK2,has been identified in patients with FOP.We report here that four structurally related compounds,lucilactaene,hydroxylucilactaene,NG-391 and NG-393,produced by fungal strain Fusarium sp.B88,inhibit BMP signaling in vitro.Alkaline phosphatase activity,a marker enzyme of osteoblastic differentiation,was decreased in C2C12 myoblasts stably expressing mutant ALK2 by treatment with those compounds with IC_(50) values of 5.7,6.8,6.9 and 6.1 mM,respectively.Furthermore,NG-391 and NG-393 inhibited BMP-specific luciferase reporter activity,which is directly regulated by transcription factor Smads,with IC50 values of 1.4 and 2.1 mM,respectively.These findings suggest that these fungal metabolites may provide a new direction in the development of FOP therapeutics.