Beauvericin was analyzed in three forms of the Lepidoptra pathogenic fungus Isaria tenuipes(4 isolates):(a)natural specimen,(b)cultivated synnemata on rice media,and(c)mycelia from fermentation in liquid media.Beauver...Beauvericin was analyzed in three forms of the Lepidoptra pathogenic fungus Isaria tenuipes(4 isolates):(a)natural specimen,(b)cultivated synnemata on rice media,and(c)mycelia from fermentation in liquid media.Beauvericin was detected in very low amounts in all tested natural specimens.Synnemata on rice contained much higher concentrations of beauvericin than the corresponding natural materials,although the concentrations were lower than mycelia from liquid fermentation.The results casted a caution that beauvericin concentration should be carefully checked,as a possible toxic constituent,upon mass production of a selected strain of Isaria tenuipes for health food purposes.展开更多
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 ...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.展开更多
Beauvericin, a cyclohexadepsipeptide-possessing natural product with synergistic antifungal, insecticidal, and cytotoxic activities. We isolated and characterized the fpBeas gene cluster, devoted to beauvericin biosyn...Beauvericin, a cyclohexadepsipeptide-possessing natural product with synergistic antifungal, insecticidal, and cytotoxic activities. We isolated and characterized the fpBeas gene cluster, devoted to beauvericin biosynthesis, from the filamentous fungus Fusarium proliferatum LF061. Targeted inactivation of the F. proliferatum genomic copy of fpBeas abolished the production of beauvericin. Comparative sequence analysis of the FpBEAS showed 74% similarity with the BbBEAS that synthesizes the cyclic trimeric ester beauvericin in Beauveria bassiana, which assembles N-methyl-dipeptidol monomer intermediates by the programmed iterative use of the nonribosomal peptide synthetase modules. Differences between the organization of the beauvericin loci in F. proliferaturm and B. bassiana revealed the mechanism for high production of beauvericin in F. proliferatum. Our work provides new insights into beauvericin biosynthesis, and may lead to beauvericin overproduction and creation of new analogs via synthetic biology approaches.展开更多
Objective To isolate and identify the chemical constituents from mycelia and spores of the fungus Cordyceps cicadae,respectively.Methods The chemical constituents were isolated and purified by repeated silica gel,Seph...Objective To isolate and identify the chemical constituents from mycelia and spores of the fungus Cordyceps cicadae,respectively.Methods The chemical constituents were isolated and purified by repeated silica gel,Sephadex LH-20,and reversed phase HPLC.The structures of these compounds were elucidated on the basis of extensive spectroscopic analysis,including 1 D and 2D NMR.Results Nine known sterols such as ergosterol（1）,ergosterol peroxide（2）,9,11-dehydroergosterol peroxide（3）,3β,5α,9α-trihydroxy-（22E,24R）-ergosta-7,22-dien-6-one（4）,3β,5α,9α,14α-tetrahydroxy-（22E,24R）-ergosta-7,22-dien-6-one（5）,5 α,6α-e poxy-（22 E,,24 R）-e rgosta-8（14）,22-diene-3α,7α-diol （6）, 3β,5α,6β-（22E,24R）-ergosta-7,22-dien-3,5,6-triol （7）, 3β,5α,6α-6- methoxyergosta-（22E,24R）-7,22-diene-3,5-diol （8）, 4-hydroxy-17R-methylincisterol （9）, together with a resorcinol derivative, 5-n-nonadecylresorcinol （10）, a cydo- desipeptide, beauvericin （11）, and a nucleoside, N^6-（2-hydroxyethyl）adenosine （12） were successively isolated from the cultivated C. cicadaemycelia and spores. Conclusion Compounds 3-10 are reported for the first time from the title sample, beauvericin exhibits significant cytotoxicity against human leukemia cell line and human lung cancer cell line.展开更多
基金Financial support from the National Center for Genetic Engineering and Biotechnology(BIOTEC)is gratefully acknowledged.
文摘Beauvericin was analyzed in three forms of the Lepidoptra pathogenic fungus Isaria tenuipes(4 isolates):(a)natural specimen,(b)cultivated synnemata on rice media,and(c)mycelia from fermentation in liquid media.Beauvericin was detected in very low amounts in all tested natural specimens.Synnemata on rice contained much higher concentrations of beauvericin than the corresponding natural materials,although the concentrations were lower than mycelia from liquid fermentation.The results casted a caution that beauvericin concentration should be carefully checked,as a possible toxic constituent,upon mass production of a selected strain of Isaria tenuipes for health food purposes.
基金the National Program on Key Basic Research Project(973program,2013CB734000)in part by grants from the National Natural Science Foundation of China[31670052,31430002,31320103911,31400090,81302678 and 31125002]+2 种基金the Ministry of Science and Tech-nology of the People’s Republic of China[2011ZX09102-011-11,2013ZX10005004-005]China Ocean Mineral Resources R&D Association(Grant No.DY125-15-T-07)the European Union’s Seventh Framework Programme(FP7/2007-2013)under grant agreement no.312184.
文摘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.
基金supported by the National Basic Research Program of China (2013CB734000, 2012CB725200)the CAS Pillar Program (XDA04074000)+1 种基金Ministry of Science and Technology of China (2011ZX11102-011-11)ZHANG LiXin is an Awardee for the National Distinguished Young Scholar Program in China
文摘Beauvericin, a cyclohexadepsipeptide-possessing natural product with synergistic antifungal, insecticidal, and cytotoxic activities. We isolated and characterized the fpBeas gene cluster, devoted to beauvericin biosynthesis, from the filamentous fungus Fusarium proliferatum LF061. Targeted inactivation of the F. proliferatum genomic copy of fpBeas abolished the production of beauvericin. Comparative sequence analysis of the FpBEAS showed 74% similarity with the BbBEAS that synthesizes the cyclic trimeric ester beauvericin in Beauveria bassiana, which assembles N-methyl-dipeptidol monomer intermediates by the programmed iterative use of the nonribosomal peptide synthetase modules. Differences between the organization of the beauvericin loci in F. proliferaturm and B. bassiana revealed the mechanism for high production of beauvericin in F. proliferatum. Our work provides new insights into beauvericin biosynthesis, and may lead to beauvericin overproduction and creation of new analogs via synthetic biology approaches.
基金National Natural Science Foundation of China(No.81520108028,81273430,41306130,81302692,41676073,81603022)SCTSM Project(No.14431901100,15431901000)+4 种基金Institutes for Drug Discovery and Development,Chinese Academy of Sciences(No.CASIMM0120152039)SKLDR/SIMM Projects(SIMM 1501ZZ-03)“Youth Innovation Promotion Association”from Chinese Academy of Sciences(No.2016258)“Young Talent Supporting Project”from China Association for Science and Technology(No.2016QNRC001)Shanghai“Pujiang Program”(No.16PJ1410600)
文摘Objective To isolate and identify the chemical constituents from mycelia and spores of the fungus Cordyceps cicadae,respectively.Methods The chemical constituents were isolated and purified by repeated silica gel,Sephadex LH-20,and reversed phase HPLC.The structures of these compounds were elucidated on the basis of extensive spectroscopic analysis,including 1 D and 2D NMR.Results Nine known sterols such as ergosterol（1）,ergosterol peroxide（2）,9,11-dehydroergosterol peroxide（3）,3β,5α,9α-trihydroxy-（22E,24R）-ergosta-7,22-dien-6-one（4）,3β,5α,9α,14α-tetrahydroxy-（22E,24R）-ergosta-7,22-dien-6-one（5）,5 α,6α-e poxy-（22 E,,24 R）-e rgosta-8（14）,22-diene-3α,7α-diol （6）, 3β,5α,6β-（22E,24R）-ergosta-7,22-dien-3,5,6-triol （7）, 3β,5α,6α-6- methoxyergosta-（22E,24R）-7,22-diene-3,5-diol （8）, 4-hydroxy-17R-methylincisterol （9）, together with a resorcinol derivative, 5-n-nonadecylresorcinol （10）, a cydo- desipeptide, beauvericin （11）, and a nucleoside, N^6-（2-hydroxyethyl）adenosine （12） were successively isolated from the cultivated C. cicadaemycelia and spores. Conclusion Compounds 3-10 are reported for the first time from the title sample, beauvericin exhibits significant cytotoxicity against human leukemia cell line and human lung cancer cell line.
