《(2)--药物微生物学课件BioactiveNaturalProductsfromAnim.pdf》由会员分享，可在线阅读，更多相关《(2)--药物微生物学课件BioactiveNaturalProductsfromAnim.pdf（14页珍藏版）》请在taowenge.com淘文阁网|工程机械CAD图纸|机械工程制图|CAD装配图下载|SolidWorks_CaTia_CAD_UG_PROE_设计图分享下载上搜索。
1、Send Orders for Reprints to reprintsbenthamscience.ae 1588 Mini-Reviews in Medicinal Chemistry,2017,17,1588-1601 REVIEW ARTICLE 1389-5575/17$58.00+.00 2017 Bentham Science Publishers Bioactive Natural Products from Animal Associated-Microbes Yuan Tian1,#,*,Yan-Ling Li1,#and Feng-Chun Zhao2 1College
2、of Life Science,Taishan Medical University,Taian,Shandong,271016,China;2College of Life Science,Shan-dong Agricultural University,Taian,Shandong,271018,China A R T I C L E H I S T O R Y Received:January 16,2016 Revised:September 24,2016 Accepted:October 10,2016 DOI:10.2174/1389557516666161024144014
3、Abstract:Objective:Animal associated-microbes are miroorganisms living inside animal hosts during some parts of their life.In view of the special environment,it is considered that the unique microbes might be the producer of new compounds with diversity biological activities.Conclusion:This review s
4、ummarizes new findings(mainly described since 2011)concerning the characteristics of various natural products that can be extracted from animal associated-microbes,highlighting that animal related microorganisms represent an underexplored reservoir for the discov-ery of molecules with unique scaffol
5、ds and promising biological activities.Keywords:Alkaloids,animal associated-microbes,bioactivity,hybrids,natural products,peptides,polyketides,terpenoids.1.INTRODUCTION Since the discovery of penicillin in 1928,bioactive me-tabolites produced by microorganisms have helped humans conquer various dise
6、ases.However,the golden age of antibi-otics was soon ended,as the multidrug-resistant and pan-resistant strains emerged 1.Moreover,the number of age-related diseases including atherosclerosis 2,type 2 diabetes 3,and Alzheimers disease 4 are increasing,and new pathogens such as Mycobacterium tubercul
7、osis 5,Ebolavi-rus 6 and Middle East respiratory syndrome coronavirus 7 are in the process of evolution.In addition,it is estimated that over 300 million people are affected by about 7000 rare diseases in the world,most of which remain out of effective control 8,9.New drugs are more urgently require
8、d than ever before,but the number of new chemical entities in the drug development pipeline is decreasing.Most of the drugs in clinical use today were discovered before 1970,with many new ones only being based on semisynthetic tailoring of these existing scaffolds 10.The limited structural diversity
9、 makes it difficult to overcome the serious situation.Accordingly,there is an urgent need for novel reagents to combat the existed and emerging diseases.Natural products still play an indispensable role in serving as inspiration for medicinal chemistry campaigns 11,12.Recently,microbes that coexist
10、with various animals such as insects,fishes and *Address correspondence to this author at the College of Life Science,Taishan Medical University,Taian,Shandong,271016,China;Tel/Fax:+86-358-623-1086;E-mail:#Authors contributed equally.invertebrates are receiving renewed attention for their pro-ductio
11、n of novel agents with unprecedented architectures and potent bioactivities,presumably as a result of their long coevolution with hosts 13,14.These animal associated-microbes always possess multi-ple metabolic pathways 15,16,and generate a lot kind of natural products including polyketides 17,peptid
12、es 18,terpenoids 19 and so on.Many of the compounds have provided considerable clue to discover new drugs,and some of them have become important lead molecules.For exam-ple,fingolimod 1(Fig.1),the first-line treatment for multi-ple sclerosis,was originally derived from myricocin 2,a molecule produce
13、d by insect symbiont Cordyceps sinensisa 12.HONH2HOHOHOOCNH2OHOHO12 Fig.(1).The structures of compounds 1-2.Recently,a vast amount of new biological natural com-pounds with various activities,such as anti-bacteria,anti-Bioactive Natural Products from Animal Associated-Microbes Mini-Reviews in Medici
14、nal Chemistry,2017,Vol.17,No.17 1589 tumor,anti-fungal and so on,have been isolated from animal associated-microbes.Natural products from this specific source have been the subject of several review articles.In 2009,Li reviewed pharmaceutical metabolites derived from microbial symbionts in China Sea
15、 20.In 2013,Pejin and his co-workers reviewed antitumor natural products from marine symbiotic fungi 21.In 2015,bioactive products from insect and invertebrate associated microbes have been reviewed by Choi and Oh 15.While in the same year,Challinor and Bode published a review on natural products is
16、olated from novel microbial sources,which included some animal associated-microbes 16.This review is intended to highlight an overview about the unique biological and chem-istry functions of animal associated-microbes derived natural products(mainly described since 2011),with a brief outlook in the
17、end.2.POLYKETIDES Owing to the unpredictable chemodiversity,polyketides have occupied a unique region of chemical and pharmaceutical field.Source analysis of approved small molecule drugs in-dicates that polyketides are approximately five times more likely to possess drug activity than other natural
18、 product categories 22,23,and animal associated-microbes provide a valuable source of this kind of molecules.A marine-derived fungus Aspergillus sp.from a gorgo-nian Dichotella gemmacea could generate two novel benzy-lazaphilone derivatives with an unprecedented carbon skele-ton,aspergilone A 3(Fig.
19、2),and its symmetrical dimer,as-pergilone B 4.Compound 3 not only exhibited in vitro selec-tive cytotoxicity but also showed potent antifouling activity 24.From the culture broth of another gorgonian symbiotic fungus Cochliobolus lunatus,three new 14-membered resor-cylic acid lactones,named cochliom
20、ycins A-C 5-7,were isolated 25.Both compounds 5 and 6 own a rare natural acetonide group,and compound 7 possess a 5-chloro-substituted lactone.These lactones were evaluated against the larval settlement of barnacle Balanus amphitrite,and compound 5 showed potent inhibition activity 25.Subse-quently,
21、cochliomycins D-F 8-10,were isolated from a sea anemone-derived fungus Cochliobolus lunatus.Like com-pound 5,compounds 8 and 10 were also able to inhibit the larval of barnacle Balanus amphitrite from settling down 26.A marine-derived fungus Stachylidium sp.,isolated from a sponge Callyspongia sp.,l
22、ed to the discovery of three new phthalide derivatives,marilones A-C 11-13(Fig.3).The skeleton of compounds 11 and 12 was very unusual.Com-pound 11 was found to have antiplasmodial activity against Plasmodium berghei with an IC50 value of 12.1 M,and 12 showed selective antagonistic activity towards
23、the serotonin receptor 5-HT2B with a Ki value of 7.7 M 27.Chemical examination of another sponge-associated fungus Emericella variecolor resulted in the characterization of seven new polyketide derivatives,namely,varioxiranols A-G 14-20,and a new hybrid PKS-isoprenoid metabolite,19-O-methyl-22-metho
24、xypre-shamixanthone 21,together with seven known analogues 22-28.Compounds 19 and 20 were found for the first time to link a xanthone moiety with a benzyl alcohol via an ether bond,while the dioxolanone group of 18 was unusual in nature.A cell-based lipid-lowering assay revealed that 25 exerted sign
25、ificant inhibition against lipid accumulation in HepG2 cells without cytotoxic effects,ac-companying potent reduction of total cholesterol and triglyc-erides 28.Investigation of secondary metabolites from a sea fan-derived fungus Curvularia sp.PSU-F22 resulted in three new metabolites,curvulapyrone
26、29(Fig.4),curvulalide 30 and curvulalic acid 31 together with six known compounds 32-37.Their antimicrobial activity against Staphylococcus aureus(SA),methicillin-resistant SA(MRSA)and Mi-crosporum gypseum were examined.Unfortunately,none of them were active against the strains at the initial concen
27、tra-tion of 200 g/mL 29.From another sea fan-derived fungus Nigrospora sp.PSU-F5,four new metabolites,nigrospoxydons A-C 38-40 and nigrosporapyrone 41 were isolated.Only com-pound 38 showed medium activity against SA(MIC=64 g/mL)30.OOOOOHMeOOH5OOOOOHMeOOH6OOOHOHOHMeOOH7OOHH3COOOHOHOOOHH3COOOHOHOOOHH
28、3COOOHOHO8910OOOOOOOOO34 Fig.(2).The structures of compounds 3-10.1590 Mini-Reviews in Medicinal Chemistry,2017,Vol.17,No.17 Tian et al.OOMeOO11OOMeOHO12OOMeOO13OHOHOMeOHOHOHOMeOHOHOHOHOHOMeOHOHOMeOHOHOMeOHOHClOHOOMeOHOOHOOHOHOMeOHOHOMeOHOOHOHOHOMeOHOHOOHMeOOHOOOOH OHOHOOHMeOOHOOOOH OHOOOHOOHOOOOHOO
29、HOOMeOMeOOHOOHOOHOHOOOHHOOHOMeMeOOOOHHOOHHO141516171822231920212425262728 Fig.(3).The structures of compounds 11-28.Chemical investigation of a mantis-associated fungus Daldinia eschscholzii led to the characterization of two novel immunosuppressive dalesconols A 42 and B 43(Fig.5).Op-tical resoluti
30、on of 42 and 43 by chiral HPLC gave the corre-sponding enantiomers(+)-42 and(-)-42,as well as(+)-43 and(-)-43 31.Subsequently,the scaled-up fermentation of the same fungus was found to simultaneously generate four novel carbon skeletons,illustrated by daeschol A 44,dalma-nol A 45,acetodalmanols A 46
31、 and B 47.These metabolites were separated by chiral HPLC to obtain the optically pure enantiomers.Compounds(+)-44,(+)-45,(-)-45,46,(+)-47 and(-)-47 were substantially immunosuppressive with the IC50 values of 5.96,0.025,1.72,5.56,5.00,0.87,and 2.14 g/mL,respectively,which is quite comparable to tha
32、t(0.06 g/mL)of cyclosporin A 32.Furthermore,using precursor-directed biosynthesis and mutational biosynthesis,a skele-tally new polyketide-alkaloid hybrid molecule and four ni-trogenated polyketides,namely,dalesindole 48 and muta-dalesols C-F 49-52,were obtained from this fungus 33,34.Chiral HPLC pr
33、eparation of compound 48 resulted in four Bioactive Natural Products from Animal Associated-Microbes Mini-Reviews in Medicinal Chemistry,2017,Vol.17,No.17 1591 enantiomers 48a-48d.Compounds 48a,48b and 48d exhib-ited broad and good potency against clinical bacterial strains Clostridium difficile,Vei
34、llonella sp.,Prevotella buccae,Bac-teroides fragilis,and Peptostreptococcus sp.with IC50 values of 5.0 M,respectively,and 48c showed selective inhibition against C.difficile and Veillonella sp.(IC50=5.0 M)33.The chiral HPLC separation of compounds 50 and 52 af-forded(+)-50,(-)-50 and(+)-52,(-)-52,re
35、spectively.How-ever,none of the four mutadalesols showed bioactivities 34.Recently,a new chlorinated pentacyclic polyketide,daldinone E 53,was purified from Daldinia sp.treated with the epigenetic modifier suberoylanilide hydroxamic acid(SAHA).A biosynthetically related epoxide-containing dald-inone
36、 analogue 54,was also purified from the same fungus.Both compounds 53 and 54 displayed DPPH radical scav-enging activity with potency comparable to the positive con-trol ascorbic acid 35.A structurally unprecedented cyclobutane-bearing tri-cyclic lactam metabolite,tripartilactam 55(Fig.6),was pro-du
37、ced by Streptomyces sp.in a dung beetles brood ball,and was demonstrated as a Na+/K+ATPase inhibitor(IC50=16.6 g/mL)36.Two new dimeric anthraquinones named torru-biellins A 56 and B 57,were characterized from the broth of leaf hopper pathogenic fungus Torrubiella sp.BCC 28517.Compound 56 exhibited e
38、xtensive range of biological activi-ties including antimalarial activity against Plasmodium falci-patum K1(IC50=0.33 g/mL),antifungal activity against Candida albicans(IC50=1.66 g/mL),and antibacterial ac-tivity against Bacillus cereus(MIC=6.25 g/mL)37.Three new compounds,paecilomycones A,B,and C 58
39、-60,with effective inhibition against diphenolase were obtained from methanol extract of liquid-cultivated mycelia of ento-mopathogenic fungus Paecilomyces gunnii.Structure and activity studies showed that their tyrosinase inhibition activi-ties are positively related to the number of hydroxyl group
40、s on the paecilomycones 38.Opaliferin 61,a polyketide with a unique partial structure in which a cyclopentanone and tetrahydrofuran were connected with an external double bond,was isolated from the insect pathogenic fungus Cordy-ceps sp.NBRC 106954.It showed only weak cytotoxicity against three tumo
41、r cell lines(HSC-2,HeLa,and RERF-LC-KJ)39.3.ALKALOIDS The druggability of small organic molecules generally follows the rule of 5 40,which depends heavily on how heteroatoms such as nitrogen are incorporated or positioned in molecules 41.Thus alkaloids usually have a higher hit rate for bioactive/le
42、ad molecules 42.Animal associated-microbes have been evidenced to produce a large amount of alkaloids.White croaker derived Curvularia sp.IFB-Z10 generated a skeletally unprecedented alkaloid named curvulamine 62 OOHOHOOHOHOOOHOHOHOOOHOHHOOHOOOOHOOOOOOOH3629303132333435HOOOHOHHOOOOOMeOOOOHOOHHOOOOHH
43、OOOHOOH383940OOHHOHO37OOHOHOOOMeOHO41 Fig.(4).The structures of compounds 29-41.1592 Mini-Reviews in Medicinal Chemistry,2017,Vol.17,No.17 Tian et al.(Fig.7)incorporating two undescribed extender units.Com-pound 62 showed selective antibacterial activity against four clinical anaerobic bacteria incl
44、uding Veillonella parvula,Streptococcus sp.,Bacteroides vulgatus,and Peptostrepto-coccus sp.with MIC values at 0.37 M 43.An Aspergillus sp.obtained from the Mediterranean sponge produced seven new alkaloids,tryptoquivaline K 63 and fumiquinazolines K-P 64-69 bearing a rare 1-aminocyclopropane-1-carb
45、oxylic acid residue,with six known compounds including a cyto-toxic compound fumiquinazoline J 70 44.From a coral-associated fungus Aspergillus versicolor LCJ-5-4,cottoquinazoline D 71(Fig.7),a new alkaloid with a rare 1-aminocyclopropane-1-carboxylic acid residue,was identified together with two ne
46、w quinazolinone alkaloids,cottoquinazolines B 72 and C 73.Compound 72 showed medium inhibition against Candida albicans with an MIC value of 22.6 M 45.Using direct analysis in real time(DART)mass spectrometry,new halogenated prenyl-indole alkaloids were detected from hyphae of an invertebrate-derive
47、d Malbranchea graminicola,without the need for any organic extraction.Subsequently,two novel chlorinated metabolites,named(-)-spiromalbramide 74 and(+)-isomalbrancheamide B 75,were isolated from liquid culture in artificial seawater.Remarkably,two new brominated analogues,(+)-malbrancheamide C 76 an
48、d(+)-isomalbran-cheamide C 77,were produced by enriching the growth me-dium with bromine salts 46.OOHOHOOHO(+)-42(19S,28R)(-)-42(19R,28S)OOHHOOHOOHO1928(+)-43(19R,28R)(-)-43(19S,28S)1928OOHHOOHOOHO23(+)-46(2S,3R)(-)-46(2R,3S)OOHOHOOHOOHHOOH232(+)-47(2R,3R,2R)(-)-47(2S,3S,2S)OOHHOHOOHOO(+)-44(8S,19S,
49、28S,29R)(-)-44(8R,19R,28R,29S)1928829OOHHOOHOOH(+)-45(2S,3R)(-)-45(2R,3S)23HNOHOO4951NHOOOHNHOHO(+)-50(2S)(-)-50(2R)NHOOHO48a(2S,3S)48b(2R,3R)48c(2R,3S)48d(2S,3R)OHNHNOHO232(+)-52(2R)(-)-52(2S)2HOHOClHOOOHOH53HOHOOOHOH54O Fig.(5).The structures of compounds 42-54.Bioactive Natural Products from Anim
50、al Associated-Microbes Mini-Reviews in Medicinal Chemistry,2017,Vol.17,No.17 1593 HNOOOOHOHOH55OOOHOHOHOHOOHHOOOHOHOHOHOOHHHOHO5657OHRHOHOOMeOOOOOOMeOHH58 R=OH60 R=NH259OOOOHOOH61 Fig.(6).The structures of compounds 55-61.Metabolites investigation of spider pathogenic fungus Torrubiella sp.BCC 2165