探索抗生素的本质（英文PPT）Probing Nature for Antibiotics.ppt

probingnatureforantibiotics iroshanayanthikanawarathnemichiganstateuniversity04 30 08 struggleforliving www photos screensaver www creswell crags org uk historyofhumankindcanberegardedfromamedicinalpointofviewasastruggleagainstinfectiousdiseases yoneyama h katsumata r biosci biotechnol biochem 2006 70 1060 survivalagainstinfectiousdiseases dodd cmcvellore ac in whatareantibiotics moleculesthatstopthemicrobialgrowth bothbacteriaandfungi orkillthemoutright walsh c antibioticsactionsoriginsandresistance 2003 4 howdotheantibioticsactagainstbacteria walsh c antibioticsactionsoriginsandresistance 2003 cellwallbiosynthesis lactams cyclosporins glycopeptides howdotheantibioticsactagainstbacteria walsh c antibioticsactionsoriginsandresistance 2003 proteinbiosynthesisaminoglycosides macrolides tetracyclines oxazolidinones howdotheantibioticsactagainstbacteria walsh c antibioticsactionsoriginsandresistance 2003 19publications nigms nih gov dnabiosynthesisquinolones rnabiosynthesisrifampicin 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wheredotheantibioticscomefrom nature np ss ts helpsindesigningthemolecules naturalproductsasantibiotics naturallyoccurringcompoundsthatareendproductsofsecondarymetabolism mostlyextractedfromplants marineorganisms ormicroorganisms singh s b barrett j f biochemicalpharmacology 2006 71 1006 naturalproductsasantibiotics naturallyoccurringcompoundsthatareendproductsofsecondarymetabolism mostlyextractedfromplants marineorganisms ormicroorganisms eg singh s b barrett j f biochemicalpharmacology 2006 71 1006pal s tetrahedron 2006 62 3171 erythromycin isolation streptomyceserythreusin1952uses respiratorytractdiseases genitalinfectionsmoa inhibitionofproteinsynthesis antibioticswhicharesemi synthesized syntheticallymodifiedchemicalcompoundswhichareoriginatedfromnaturalproducts walsh c antibioticsactionsoriginsandresistance 2003 4 erythromycinis acidunstable pal s tetrahedron 2006 62 3171 antibioticswhicharesemi synthesized clarithromycin azithromycin hmr3647 te802 pal s tetrahedron 2006 62 3171 antibioticswhicharetotallyfromsynthesis totallysynthesizedmoleculeswhicharepotentasantibiotics threemaintypes 1 sulfadrugs2 quinolones3 oxazolidinones singh s b barrett j f biochemicalpharmacology 2006 71 1006 antibioticswhicharetotallyfromsynthesis sulfadrugs sulphonamides uses urinarytractinfections pneumoniaetc moa inhibitionoffolatesynthesis harold p l o grady f w antibioticandchemotherapy 1992 6 268 272 sulfamethoxazole singh s b barrett j f biochemicalpharmacology 2006 71 1006 antibioticswhicharetotallyfromsynthesis sulfadrugs sulphonamides naturallyoccurring uses urinarytractinfections pneumoniaetc moa inhibitionoffolicacidbiosynthesis harold p l o grady f w antibioticandchemotherapy 1992 6 268 272 sulfamethoxazole singh s b barrett j f biochemicalpharmacology 2006 71 1006walsh c antibioticsactionsoriginsandresistance 2003 80 82 p aminobenzoicacid antibioticswhicharetotallyfromsynthesis quinolones ciprofloxacin uses urinarytractinfections lowerrespiratoryinfections gastrointestinalinfectionsmoa inhibitionofdnasynthesis singh s b barrett j f biochemicalpharmacology 2006 71 1006 antibioticswhicharetotallyfromsynthesis quinolonesnaturallyoccurring ciprofloxacin uses urinarytractinfections lowerrespiratoryinfections gastrointestinalinfectionsmoa inhibitionofdnasynthesis singh s b barrett j f biochemicalpharmacology 2006 71 1006kunze b hofle g reichenbach h j antibiotics 1987 40 258 aurachinc aurachind antibioticswhicharetotallyfromsynthesis oxazolidinones ford c w zurenko g e barbachyn m r currentdrugtargets infectiousdisorders 2001 1 181 linezolid uses softtissueinfections skininfections tuberculosisetc moa inhibitionofproteinsynthesis antibioticswhicharetotallyfromsynthesis oxazolidinonesnaturallyoccurring ford c w zurenko g e barbachyn m r currentdrugtargets infectiousdisorders 2001 1 181zappia g etal mini reviewsinmedicinalchemistry 2007 7 389 linezolid uses softtissueinfections skininfections tuberculosisetc moa inhibitionofproteinsynthesis cytoxazone sreptazolin sourcesofantibacterialdrugsfrom1981to2002 newman d j cragg g m snader k m j nat prod 2003 66 1022 waysofprobingnatureforantibiotics waysofprobingnatureforantibiotics newantibioticsnewarchitecturalscaffolds approacha conventionalwayofnpdiscovery singh s b barrett j f biochemicalpharmacology 2006 71 1006www spc int www oceanexplorer noaa gov extractiontothesolvents isolationandstructureelucidation naturalmaterials bioassayguidedfractionation approacha conventionalwayofnpdiscoverywhyisn titsuccessful problemsassociatedwiththegrowthortheavailabilityofthesourcereplicationofthehitsdonotdistinguishnovelfromoldmostlymissthenovelcompoundsduetothelackofsensitivitynohintsaboutmoacannotrevealpotencyatscreeningstage singh s b barrett j f biochemicalpharmacology 2006 71 1006clardy j fischbach m a walsh c nat rev biotechnol 2006 24 1541 approacha whatarethenewstrategiestoexplorenaturefornps molecularbiologybasedtechniques novelculturingtechniques heterologousexpressionofbiosyntheticgenes metagenomics genomicsandcombinatorialbiosynthesis precursordirectedbiosynthesis mutasynthesis differentialsensitivityscreeningapproach singh s b barrett j f biochemicalpharmacology 2006 71 1006clardy j fischbach m a walsh c nat rev biotechnol 2006 24 1541donadio s chemistry biology 2006 13 560 approacha whatarethenewstrategiestoexplorenaturefornps molecularbiologybasedtechniques novelculturingtechniques heterologousexpressionofbiosyntheticgenes metagenomics genomicsandcombinatorialbiosynthesis precursordirectedbiosynthesis mutasynthesis differentialsensitivityscreeningapproach singh s b barrett j f biochemicalpharmacology 2006 71 1006clardy j fischbach m a walsh c nat rev biotechnol 2006 24 1541donadio s chemistry biology 2006 13 560 approacha extractiontothesolvents producingorganismsfoundinnature pathogen precursordirectedbiosynthesis mutasynthesis wildtype mutanttype approacha precursordirectedbiosynthesis mutasynthesis 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antimicrob agentschemother 2006 50 519 producingorganismfromnature disabledtype wildtype increasedsensitivity low normal pathogen expressionofcertainprotein s targetthepathway approacha differentialsensitivityscreeningapproach fattyacidbiosynthesis agoodtarget fabtypei inmammals fabtypeii inbacteria campbell j w cronan j e jr annu rev microbiol 2001 55 305 biosynthesisofsaturatedfattyacids campbell j w cronan j e jr annu rev microbiol 2001 55 305 biosynthesisofsaturatedfattyacids campbell j w cronan j e jr annu rev microbiol 2001 55 305 biosynthesisofsaturatedfattyacids campbell j w cronan j e jr annu rev microbiol 2001 55 305 singh s b etal j am chem soc 2006 128 11916forsyth r a molecularbiology 2002 43 1387wang j etal antimicrob agentschemother 2006 50 519 approacha rna mediatedgenesilencingtechnique differentialsensitivityscreeningapproach reducedornofabfexpression 5 auggccuggacuuca 3 3 uaccggacctgttgu 5 dsrna degradationoffabfmrnaorinhibitionoftranslation inprokaryotes highersensitivitytowardsfabfinhibitors singh s b etal j am chem soc 2006 128 11916forsyth r a molecularbiology 2002 43 1387wang j etal antimicrob agentschemother 2006 50 519 rna mediatedgenesilencingtechnique differentialsensitivityscreeningapproach approacha approacha differentialsensitivityscreeningapproach results rna mediatedgenesilencingtechnique wildtypefabfanti sense wang j etal nature 2006 441 358 inhibitor g approacha differentialsensitivityscreeningapproach results rna mediatedgenesilencingtechnique wildtypefabfanti sense wildtypefabfanti sense 200timesmorepotentthancerulenin wang j etal nature 2006 441 358price a c etal thejournalofbiologicalchemistry 2001 276 6551heath r j white s w rock c o progressinlipidresearch 2001 40 467 inhibitor g approacha differentialsensitivityscreeningapproach platensimycinfromastrainofstreptomycesplatensis singh s b etal j am chem soc 2006 128 11916 discoveryofplatensimycin approacha differentialsensitivityscreeningapproach potencyofplatensimycin organismandgenotypeplatensimycinlinezolidantibacterialactivity mic g ml s aureus mssa 0 54s aureus mrsa 0 52s aureus mrsa macrolider 0 52s aureus mrsa linezolidr 132enterococcusfaecium vre 0 12 mic concentrationofinhibitorusedtoresultnovisiblegrowthofthepathogens wang j etal nature 2006 441 358 toxicity g ml helamtt ic50 1 000 100 ic50 concentrationoftheinhibitorusedtokill50 populationofthelivingcells cell freegel elongationassay wang j etal nature 2006 441 358 malonyl acp c4 1 2 acp c4 0 acp 6c acp approacha differentialsensitivityscreeningapproach highfabfselectivity heath r j nat prod rep 2002 19 581 waysofprobingnatureforantibiotics newantibioticsnewarchitecturalscaffolds approachb singh s b barrett j f biochemicalpharmacology 2006 71 1006clardy j fischbach m a walsh c nat rev biotechnol 2006 24 1541 generatingnaturemimics biosyntheticpathway designingtheoreticalchemicalspacethatfitstheactivesiteordockingthedatabasestructures translatetoarealstructurebysynthesis enzymepurification 3dstructuraldetermination approachb hutton c a perugini m a gerrard j a mol biosyst 2007 3 458hutton c a southwood t j turner j j mini reviewsinmedicinalchemistry 2003 3 115 essentialforthebacterialgrowthdoesnotexistinmammals generatingnaturemimics biosynthesisoflysine agoodtarget isoleucine threonine methionine hutton c a perugini m a gerrard j a mol biosyst 2007 3 458hutton c a southwood t j turner j j mini reviewsinmedicinalchemistry 2003 3 115 biosynthesisoflysine hutton c a perugini m a gerrard j a mol biosyst 2007 3 458hutton c a southwood t j turner j j mini reviewsinmedicinalchemistry 2003 3 115 biosynthesisoflysine approachb generatingnaturemimics hutton c a perugini m a gerrard j a mol biosyst 2007 3 458hutton c a southwood t j turner j j mini reviewsinmedicinalchemistry 2003 3 115 proposedmechanism approachb generatingnaturemimics supportivedata faehnle c r coq j l liu x viola r e journalofbiologicalchemistry 2006 281 31031cox r j gibson j s mart n m b m chembiochem 2002 3 874hutton c a southwood t j turner j j mini reviewsinmedicinalchemistry 2003 3 115 approachb generatingnaturemimics cox r j gibson j s mart n m b m chem commun 2001 1710cox r j gibson j s hadfield a t chembiochem 2005 6 2255cox r j gibson j s mart n m b m chembiochem 2002 3 874 inhibitorsoflysinebiosynthesis approachb generatingnaturemimics cox r j gibson j s mart n m b m chem commun 2001 1710cox r j gibson j s hadfield a t chembiochem 2005 6 2255cox r j gibson j s mart n m b m chembiochem 2002 3 874 inhibitorsoflysinebiosynthesis approachb generatingnaturemimics cox r j gibson j s mart n m b m chembiochem 2002 3 874cox r j gibson j s hadfield a t chembiochem 2005 6 2255 reversebiosynthesis invitroassays approachb cox r j gibson j s mart n m b m chembiochem 2002 3 874blanco j moore r a viola r e pnas 2003 100 12613han s moore r a viola r e synlett 2003 6 845 generatingnaturemimics ki asa ki phosphate directassay competitiveassays approachb generatingnaturemimics directassay cox r j gibson j s mart n m b m chembiochem 2002 3 874blanco j moore r a viola r e pnas 2003 100 12613han s moore r a viola r e synlett 2003 6 845 competitiveassays approachb generatingnaturemimics directassay cox r j gibson j s mart n m b m chembiochem 2002 3 874blanco j moore r a viola r e pnas 2003 100 12613han s moore r a viola r e synlett 2003 6 845 competitiveassays approachb cox r j gibson j s mart n m b m chembiochem 2002 3 874blanco j moore r a viola r e pnas 2003 100 12613han s moore r a viola r e synlett 2003 6 845 generatingnaturemimics directassay ki asa ki phosphate 2ndpka competitiveassays approachb generatingnaturemimics pre incubationassay cox r j gibson j s mart n m b m chembiochem 2002 3 874blanco j moore r a viola r e pnas 2003 100 12613han s moore r a viola r e synlett 2003 6 845 ki asa time dependentinhibitionassays approachb generatingnaturemimics pre incubationassay cox r j gibson j s mart n m b m chembiochem 2002 3 874blanco j moore r a viola r e pnas 2003 100 12613han s moore r a viola r e synlett 2003 6 845 time dependentinhibitionassays waysofprobingnatureforantibiotics newantibioticsnewarchitecturalscaffolds please don tflush averageamericanreceivesmorethan11prescriptionsayear about3 3billionatotal nonprescriptiondrugs halford b c ennews 2008 86 13halford b c ennews 2008 86 16 acknowledgementdr walkerdr hausingerdr arnostidr stoltzfusdr stephensoisson dr junwang merck labmates behnaz danielle joshua mark washington yemanefriends samantha sue tharanga xiaofei thankyouall back upslides approacha differentialsensitivityscreeningapproach invivostudiesofplatensimycin inamousemodelofdisseminateds aureusinfection wang j etal nature 2006 441 358 timelineofdiscoveryofnovelclassesofantibioticsandintroductioninclinic singh s b barrett j f biochemicalpharmacology 2006 71 1006 approachb generatingthenaturemimics faehnle c r coq j l liu x viola r e journalofbiologicalchemistry 2006 281 31031hutton c a perugini m a gerrard j a mol biosyst 2007 3 458hutton c a southwood t j turner j j mini reviewsinmedicinalchemistry 2003 3 115 antibioticswhicharetotallyfromsynthesis sulfadrugs sulphonamides naturallyoccurring uses urinarytractinfections pneumoniaetc moa inhibitionoffolatesynthesis harold p l o grady f w antibioticandchemotherapy 1992 6 268 272 sulfamethoxazole singh s b barrett j f biochemicalpharmacology 2006 71 1006walsh c antibioticsactionsoriginsandresistance 2003 80 82 p aminobenzoicacid approacha precursordirectedbiosynthesis nayer j h c trends biochem sci 1991 16 195nayer j h c trends biochem sci 1991 16 234kennedy j nat prod rep 2008 25 25 peni