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Die gebruik van evolusie van bakterieë teen hulself

Die gebruik van evolusie van bakterieë teen hulself


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Ons weet dat mutasies gereeld in bakterieë voorkom en ook dat een bakterie die mutasie kan kry en sterker as die ander kan word en dus oorleef, wat ook antibiotika weerstand kan veroorsaak. Kan ons doelbewus mutasies in bakterieë maak wat ander bakterieë sal benadeel, maar nie mense nie. Dit sal hulle nie net sterker maak en sodoende laat oorleef nie, maar sal die behoefte aan antibiotika verminder aangesien dit minder virulent vir mense sou wees?


Om bakterieë te muteer is 'n baie aanneemlike idee. As jy 'n spesifieke stam 'nuttige' bakterieë muteer om uiters positief geselekteer te word in die huidige omgewing, is dit moontlik dat die res van die bakterieë wat met jou nuwe gemuteerde interaksie het, swaar kompetisie sal ondervind en uiteindelik sal uitsterf.

Die groot leemte in die idee is egter dat bakterieë gereeld horisontale geenoordrag ondergaan wat hierdie idee uiters, uiters gevaarlik vir mense maak. (As jou gemuteerde bakterieë per ongeluk die gemuteerde geen oordra na byvoorbeeld 'n bakterie wat tuberkulose veroorsaak, sal dit 'n pandemie inisieer. Dit is ook ewe moontlik dat 'n gevaarlike bakterie sy gene na jou gemuteerde bakterieë kan oordra.) Dit word algemeen aanvaar. dat muterende bakterieë of ander patogene (waarvan die meeste teen hoë koerse muteer) oor die algemeen 'n slegte idee is, want sodra dit in die omgewing vrygestel word, is die moontlikhede dat die mutasie deurmekaar gaan groot word (ander mutasies kan hulle gevaarlik maak).

Horisontale geenoordrag: Oordrag van gene as gevolg van rekombinasieprosesse soos transduksie, transformasie en konjugasie wat tussen bakterieë van dieselfde of verskillende stamme, spesies, domeine kan voorkom. ens


Draai bakterieë teen hulself

Bakterieë val dikwels aan met gifstowwe wat ontwerp is om gasheerselle te kaap of selfs dood te maak. Om selfvernietiging te vermy, het bakterieë maniere om hulself teen hul eie gifstowwe te beskerm.

Nou het navorsers aan die Washington University School of Medicine in St Louis een van hierdie beskermende meganismes beskryf, wat moontlik die weg baan vir nuwe klasse antibiotika wat veroorsaak dat die bakterieë se gifstowwe op hulself draai.

Wetenskaplikes het die strukture van 'n gifstof en sy antitoksien in bepaal Streptococcus pyogenes, algemene bakterieë wat infeksies veroorsaak wat wissel van strep keel tot lewensgevaarlike toestande soos rumatiekkoors. In Strep word die antitoksien aan die gifstof gebind op 'n manier wat die gifstof onaktief hou.

"Strep moet so te sê hierdie teenmiddel uitdruk," sê Craig L. Smith, PhD, 'n postdoktorale navorser en eerste skrywer op die referaat wat 9 Februarie in die joernaal verskyn Struktuur. "As daar geen antitoksien was nie, sou die bakterieë homself doodmaak."

Met dit in gedagte, het Smith en kollegas dalk 'n manier gevind om die antitoksien onaktief te maak. Hulle het ontdek dat wanneer die antitoksien nie gebind is nie, dit van vorm verander.

"Dit is die Achilleshiel wat ons graag wil ontgin," sê Thomas E. Ellenberger, DVM, PhD, die Raymond H. Wittcoff-professor en hoof van die Departement Biochemie en Molekulêre Biofisika by die Skool vir Geneeskunde. "'n Middel wat die onaktiewe vorm van die immuniteitsfaktor sal stabiliseer, sal die gifstof in die bakterieë bevry."

In hierdie geval staan ​​die gifstof bekend as Streptococcus pyogenes beta-NAD+ glikohidrolase, of SPN. Verlede jaar het mede-outeur Michael G. Caparon, PhD, professor in molekulêre mikrobiologie, en sy kollegas in die Sentrum vir Vroue se Aansteeklike Siekte Navorsing getoon dat SPN se toksisiteit spruit uit sy vermoë om al 'n sel se winkels van NAD+ op te gebruik, 'n noodsaaklike komponent in selmetabolisme aandryf. Die antitoksien, bekend as die immuniteitsfaktor vir SPN, of IFS, werk deur SPN se toegang tot NAD+ te blokkeer, wat die bakterieë se energievoorsieningstelsel beskerm.

Met die strukture wat vasgestel is, kan navorsers nou moontlike middels toets wat die antitoksien kan dwing om ongebonde aan die gifstof te bly en sodoende die gifstof vry te laat om sy eie bakterieë aan te val.

“Die belangrikste aspek van die struktuur is dat dit ons baie vertel oor hoe die antitoksien die toksienaktiwiteit blokkeer en die bakterie spaar,” sê Ellenberger.

Om te verstaan ​​hoe hierdie bakterieë siektes by mense veroorsaak, is belangrik in geneesmiddelontwerp.

"Daar is 'n oorlog aan die gang tussen bakterieë en hul gashere," sê Smith. "Bakterieë skei gifstowwe af en ons het maniere om teenaanval deur ons immuunstelsels en met behulp van antibiotika. Maar, aangesien bakterieë antibiotika weerstand ontwikkel, moet ons nuwe generasies antibiotika ontwikkel."

Baie soorte bakterieë het hierdie toksien-antitoksienmetode ontwikkel om gasheerselle aan te val terwyl hulle hulself beskerm. Maar vandag is daar geen klasse van middels wat mik op die beskermende werking van die bakterieë se antitoksienmolekules nie.

"Natuurlik kan hulle weerstand ontwikkel sodra jy die antitoksien teiken," sê Ellenberger. "Maar dit sal 'n nuwe teiken wees. Om strukture te verstaan ​​is 'n hoeksteen van dwelmontwerp."

Storie Bron:

Materiaal verskaf deur Washington Universiteit Skool vir Geneeskunde. Oorspronklik geskryf deur Julia Evangelou Strait. Let wel: Inhoud kan geredigeer word vir styl en lengte.


Antimikrobiese interaksies: meganismes en implikasies vir geneesmiddelontdekking en weerstandsevolusie

Kombinasies van antibiotika lei tot sinergistiese en antagonistiese geneesmiddelinteraksies.

Die onderliggende meganismes van geneesmiddelinteraksies kan met behulp van nuwe tegnieke toegelig word.

Geneesmiddelinteraksies bied geleenthede vir geneesmiddelontdekking.

Multigeneesmiddelbehandelings kan evolusionêre afwykings ontgin om weerstandsevolusie te vertraag.

Algemene beginsels kan die voorspelling van sellulêre reaksies op geneesmiddelkombinasies moontlik maak.

Die kombinasie van antibiotika is 'n belowende strategie om behandelingsdoeltreffendheid te verhoog en om weerstandsontwikkeling te beheer. Wanneer dwelms gekombineer word, kan die uitwerking daarvan op selle versterk of verswak word, dit wil sê die middels kan sinergistiese of antagonistiese interaksies toon. Onlangse werk het die onderliggende meganismes van sulke geneesmiddelinteraksies aan die lig gebring deur die geneesmiddels se gesamentlike effekte op selfisiologie toe te lig. Boonop is getoon dat nuwe behandelingstrategieë wat geneesmiddelkombinasies gebruik om evolusionêre afwykings te ontgin die tempo van weerstandsevolusie op voorspelbare maniere beïnvloed. Hoë deurset studies het geneesmiddelkandidate verder geïdentifiseer op grond van hul interaksies met gevestigde antibiotika en algemene beginsels wat die voorspelling van geneesmiddelinteraksies moontlik maak, is voorgestel. Oor die algemeen ontwikkel die konseptuele en tegniese grondslag vir die rasionele ontwerp van kragtige geneesmiddelkombinasies vinnig.


Die naam Deinococcus radiodurans is afgelei van die Antieke Grieks δεινός (deinos) en κόκκος (kokkos) wat "verskriklike graan/bessie" beteken en die Latyn radius en duur, wat beteken "bestraling oorleef". Die spesie is vroeër genoem Micrococcus radiodurans. As gevolg van sy gehardheid, het dit die bynaam "Conan the Bacterium" gekry, met verwysing na Conan die Barbarian. [2]

Aanvanklik is dit in die genus geplaas Mikrokokke. Na evaluering van ribosomale RNA-volgordes en ander bewyse, is dit in sy eie genus geplaas Deinokok, wat nou verwant is aan die genus Termos. Die term "Deinococcus-Thermus groep" word soms gebruik om te verwys na lede van Deinokok en Termos. [3]

Deinokok is een genus van drie in die volgorde Deinokokke. D. radiodurans is die tipe spesie van hierdie genus, en die bes bestudeerde lid. Alle bekende lede van die genus is radiobestand: D. proteoliticus, D. radiopugnans, D. radiophilus, D. grandis, D. indicus, D. frigens, D. saxicola, D. marmoris, D. deserti, [4] D. geothermalis, en D. murrayi laasgenoemde twee is ook termofiel. [5]

D. radiodurans is in 1956 deur Arthur Anderson by die Oregon Landbou-eksperimentstasie in Corvallis, Oregon, ontdek. [6] Eksperimente is uitgevoer om te bepaal of blikkieskos met behulp van hoë dosisse gammastraling gesteriliseer kan word. 'n Blikkie vleis is blootgestel aan 'n dosis bestraling wat vermoedelik alle bekende vorme van lewe doodmaak, maar die vleis het daarna bederf, en D. radiodurans geïsoleer was.

Die volledige DNA-volgorde van D. radiodurans is in 1999 deur The Institute for Genomic Research gepubliseer. 'n Gedetailleerde aantekening en ontleding van die genoom het in 2001 verskyn. [3] Die opeenvolgende stam was ATCC BAA-816.

Deinococcus radiodurans het 'n unieke kwaliteit waarin dit beide enkel- en dubbelstring DNA kan herstel. Wanneer skade aan die sel sigbaar is, bring dit die beskadigde DNS in 'n kompartementele ringagtige struktuur waar die DNS herstel word, en is dan in staat om die nukleoïede van die buitekant van die kompartement met die beskadigde DNS te versmelt. [7]

In Augustus 2020 het wetenskaplikes berig dat bakterieë van die aarde, veral Deinococcus radiodurans bakterieë, is gevind om vir drie jaar in die buitenste ruimte te oorleef, gebaseer op studies wat op die Internasionale Ruimtestasie (ISS) gedoen is. Hierdie bevindinge ondersteun die idee van panspermia, die hipotese dat lewe regdeur die Heelal bestaan, op verskeie maniere versprei, insluitend ruimtestof, meteoroïede, asteroïdes, komete, planetoïede of besmette ruimtetuie. [8] [9] In Oktober 2020 is verwante studies na een jaar van blootstelling buite die ISS gerapporteer. [10]

D. radiodurans is 'n taamlik groot, sferiese bakterie, met 'n deursnee van 1,5 tot 3,5 μm. [11] Vier selle kleef gewoonlik aan mekaar en vorm 'n tetrad. Die bakterieë word maklik gekweek en blyk nie siekte te veroorsaak nie. [3] Onder gekontroleerde groeitoestande kan selle van dimeer-, tetrameer- en selfs multimeer-morfologieë verkry word. [11] Kolonies is glad, konveks en pienk tot rooi van kleur. Die selle kleur Gram-positief, hoewel die selomhulsel daarvan ongewoon is en aan die selwande van Gram-negatiewe bakterieë herinner. [12]

D. radiodurans vorm nie endospore nie en is nie-beweeglik. Dit is 'n verpligte aërobiese chemo-organoheterotroof, dit wil sê dit gebruik suurstof om energie van organiese verbindings in sy omgewing te verkry. Dit word dikwels gevind in habitatte wat ryk is aan organiese materiale, soos riool, vleis, ontlasting of grond, maar is ook geïsoleer van mediese instrumente, kamerstof, tekstiele en gedroogde kosse. [12]

Dit is uiters bestand teen ioniserende straling, ultraviolet lig, uitdroging en oksiderende en elektrofiele middels. [13]

Sy genoom bestaan ​​uit twee sirkelvormige chromosome, een 2,65 miljoen basispare lank en die ander 412 000 basispare lank, asook 'n megaplasmied van 177 000 basispare en 'n plasmied van 46 000 basispare. Dit het ongeveer 3 195 gene. In sy stilstaande fase bevat elke bakteriese sel vier kopieë van hierdie genoom wanneer dit vinnig vermenigvuldig word, elke bakterie bevat 8-10 kopieë van die genoom.

D. radiodurans is in staat om 'n akute dosis van 5 000 grys (Gy), of 500 000 rad, van ioniserende straling te weerstaan ​​met byna geen verlies aan lewensvatbaarheid nie, en 'n akute dosis van 15 000 Gy met 37% lewensvatbaarheid. [14] [15] [16] 'n Dosis van 5 000 Gy sal na raming etlike honderde dubbelstring-breuke (DSB's) in die organisme se DNA inbring (

0,005 DSB/Gy/Mbp (haploïede genoom)). Ter vergelyking, 'n borskas X-straal- of Apollo-sending behels ongeveer 1 mGy, 5 Gy kan 'n mens doodmaak, 200-800 Gy sal doodmaak E coli, en meer as 4 000 Gy sal die stralingsbestande tardigrade doodmaak.

Verskeie bakterieë met vergelykbare radioweerstand is nou bekend, insluitend sommige spesies van die genus Chrookokkidiopsis (filum sianobakterieë) en sommige spesies van Rubrobacter (phylum actinobacteria) onder die archaea, die spesie Thermococcus gammatolerans toon vergelykbare radioweerstand. [5] Deinococcus radiodurans het ook 'n unieke vermoë om beskadigde DNA te herstel. Dit isoleer die beskadigde segmente in 'n beheerde area en herstel dit. Hierdie bakterieë kan ook baie klein fragmente van 'n hele chromosoom herstel. [17]

Deinokok bereik sy weerstand teen bestraling deur veelvuldige kopieë van sy genoom en vinnige DNA-herstelmeganismes te hê. Dit herstel gewoonlik breuke in sy chromosome binne 12–24 uur deur 'n 2-stap proses. Eerstens, D. radiodurans herverbind sommige chromosoomfragmente deur 'n proses wat enkelstrengig uitgloeiing genoem word. In die tweede stap herstel veelvuldige proteïene dubbelstrengbreuke deur homoloë rekombinasie. Hierdie proses stel nie meer mutasies in as wat 'n normale rondte van replikasie sou doen nie.

Skandeerelektronmikroskopie-analise het getoon dat DNA in D. radiodurans is georganiseer in diggepakte toroïede, wat DNA-herstel kan vergemaklik. [18]

’n Span Kroatiese en Franse navorsers onder leiding van Miroslav Radman het gebombardeer D. radiodurans om die meganisme van DNA-herstel te bestudeer. Ten minste twee kopieë van die genoom, met ewekansige DNS-breuke, kan DNS-fragmente deur uitgloeiing vorm. Gedeeltelik oorvleuelende fragmente word dan gebruik vir sintese van homoloë streke deur 'n bewegende D-lus wat verlenging kan voortduur totdat die fragmente komplementêre vennootstringe vind. In die laaste stap is daar oorkruising deur middel van RecA-afhanklike homoloë rekombinasie. [19]

D. radiodurans is in staat tot genetiese transformasie, 'n proses waardeur DNA afkomstig van een sel deur 'n ander sel opgeneem en geïntegreer kan word in die ontvangergenoom deur homoloë rekombinasie. [20] Wanneer DNS-skade (bv. pirimidiendimere) deur UV-bestraling in skenker-DNS ingebring word, herstel die ontvangerselle die skade in die transformerende DNS doeltreffend, soos in sellulêre DNS, wanneer die selle self bestraal word.

Michael Daly het voorgestel dat die bakterie mangaankomplekse as antioksidante gebruik om homself teen stralingskade te beskerm. [21] In 2007 het sy span gewys dat hoë intrasellulêre vlakke van mangaan(II) in D. radiodurans beskerm proteïene teen oksidasie deur bestraling, en hulle het die idee voorgestel dat "proteïen, eerder as DNA, die hoofteiken is van die biologiese werking van [ioniserende straling] in sensitiewe bakterieë, en uiterste weerstand in Mn-akkumulerende bakterieë is gebaseer op proteïen beskerming". [22] In 2016, Massimiliano Peana et al. het 'n spektroskopiese studie deur KMR-, EPR- en ESI-MS-tegnieke gerapporteer oor die Mn(II)-interaksie met twee peptiede, DP1 (DEHGTAVMLK) en DP2 (THMVLAKGED), waarvan die aminosuursamestelling gekies is om die meerderheid van die mees algemene aminosuur in te sluit. sure teenwoordig in 'n Deinococcus radiodurans bakterie selvrye uittreksel wat komponente bevat wat in staat is om uiterste weerstand teen ioniserende straling te verleen. [23] In 2018 het M. Peana en C. Chasapis gerapporteer deur 'n gekombineerde benadering van bioinformatiese strategieë gebaseer op strukturele data en annotasie, die Mn(II)-bindende proteïene wat deur die genoom van DR gekodeer is en 'n model vir Mangaan-interaksie met DR-proteoomnetwerk betrokke by ROS-reaksie en verdediging. [24]

'n Span Russiese en Amerikaanse wetenskaplikes het voorgestel dat die radioweerstand van D. radiodurans 'n Mars-oorsprong gehad. Hulle het voorgestel dat evolusie van die mikro-organisme op die Mars-oppervlak kon plaasgevind het totdat dit op 'n meteoriet aan die aarde afgelewer is. [25] Afgesien van sy weerstand teen straling, Deinokok is geneties en biochemies baie soortgelyk aan ander aardse lewensvorme, wat argumenteer teen 'n buiteaardse oorsprong wat nie algemeen by hulle is nie.

In 2009 is berig dat stikstofoksied 'n belangrike rol speel in die bakterieë se herstel van blootstelling aan straling: die gas word benodig vir verdeling en verspreiding nadat DNA-skade herstel is. ’n Geen is beskryf wat stikstofoksiedproduksie na UV-bestraling verhoog, en in die afwesigheid van hierdie geen kon die bakterieë steeds DNA-skade herstel, maar wou nie groei nie. [26]

'n Aanhoudende vraag t.o.v D. radiodurans is hoe so 'n hoë mate van radioweerstand kan ontwikkel. Natuurlike agtergrondstralingsvlakke is baie laag—in die meeste plekke, in die orde van 0,4 mGy per jaar, en die hoogste bekende agtergrondstraling, naby Ramsar, Iran is slegs 260 mGy per jaar. Met natuurlike agtergrondbestralingsvlakke wat so laag is, is organismes wat meganismes ontwikkel spesifiek om die gevolge van hoë bestraling af te weer, onwaarskynlik.

Valerie Mattimore van Louisiana State University het die radioweerstand van D. radiodurans is bloot 'n newe-effek van 'n meganisme vir die hantering van langdurige sellulêre uitdroging (droogheid). Om hierdie hipotese te ondersteun, het sy 'n eksperiment uitgevoer waarin sy gedemonstreer het dat mutantstamme van D. radiodurans wat hoogs vatbaar is vir skade deur ioniserende straling is ook hoogs vatbaar vir skade van langdurige uitdroging, terwyl die wildtipe stam weerstand teen beide is. [27] Benewens DNA herstel, D. radiodurans gebruik LEA-proteïene (Late Embryogenesis Abundant proteins) [28] uitdrukking om teen uitdroging te beskerm. [29]

In hierdie konteks ook die robuuste S-laag van D. radiodurans deur sy hoofproteïenkompleks, die S-laag Deinoxanthin Binding Complex (SDBC), dra sterk by tot sy uiterste radioweerstand. Trouens, hierdie S-laag dien as 'n skild teen elektromagnetiese spanning, soos in die geval van blootstelling aan ioniserende straling, maar stabiliseer ook die selwand teen moontlike gevolglike hoë temperature en uitdroging. [30] [31]


Selfmoordbakterieë: Bioloë bestudeer eensellige organismes wat hulself af en toe met 'n gifstof vergiftig

'n Tipiese vloeibare kultuur van die sianobakterie Synechocystis.

Die sianobakterie Synechocystis produseer gifstowwe wat dikwels tot sy eie ondergang lei. Die bioloë Stefan Kopfmann en prof. dr. Wolfgang Hess van die Universiteit van Freiburg het die logika bepaal wat hierdie meganisme beheer. Hul bevindinge is in die bekende tydskrifte gepubliseer. Tydskrif vir Biologiese Chemie (JBC) en Openbare Biblioteek van Wetenskap (PLoS EEN).

Die sianobakterie Synechocystis produseer verskeie gifstowwe. Die meeste van die tyd kan hulle egter nie aktief raak nie omdat die eensellige organisme hulle gewoonlik net saam met 'n antitoksien produseer wat hul giftige effek neutraliseer. Dit is 'n truuk van die natuur: Die gene vir die toksien en die antitoksien is saam op 'n plasmied geleë, dit wil sê 'n fragment van DNS wat onafhanklik van die werklike bakteriese chromosoom bestaan. In teenstelling met die toksien, is die antitoksien nie baie stabiel nie. Wanneer 'n sel die plasmied tydens seldeling verloor, gaan albei die gene verlore. Aangesien die toksien meer stabiel is as die antitoksien en dus vir 'n langer tydperk effektief is, sterf hierdie selle uiteindelik af. Die toksien-antitoksienpare vorm dus 'n natuurlike seleksiemeganisme wat sorg dat slegs selle wat die plasmied behou, oorleef.

Die plasmied pSYSA van die sianobakterie Synechocystis het nie een nie maar sewe verskillende stelsels van hierdie soort en is dus goed beskerm. Die rede hiervoor is omdat die plasmied pSYSA, benewens die gene vir die sewe toksien-antitoksienpare, die genetiese inligting vir 'n bakteriese immuunstelsel besit. As die plasmied met hierdie stelsel in seldeling verlore raak, sorg verskeie gifstowwe dus dat die bakterie doodgemaak word. Die feit dat die gene wat daarvoor verantwoordelik is gekombineer word met 'n hoë hoeveelheid toksien-antitoksienpare, dui daarop dat hierdie sisteem spesiale betekenis het vir die sianobakteriese sel.


Bakterieë 'skuifel' hul genetika rond om antibiotika weerstand te ontwikkel op aanvraag

Om weerstand teen antibiotika te stop, moet wetenskaplikes weet hoe bakterieë weerstandig word. Krediet: Jarun Ontakrai/ Shutterstock

Antibiotiese weerstand - die vermoë van skadelike bakterieë om behandeling deur antibiotika te oorleef - is 'n groeiende bedreiging. Dit maak dit moeiliker om lewensgevaarlike infeksies te behandel, insluitend tuberkulose, MRSA en gonorree - en verhoog die risiko's van selfs geringe chirurgie.

Ten einde antibiotika weerstand op te los, een ding wat navorsers eers moet verstaan, is hoe om weerstand te keer om te begin gebeur. ’n Onlangse studie wat ek met kollegas aan die Universiteit van Oxford gedoen het, het gehelp om daardie begrip te verhoog deur te wys dat bakterieë hul genetika slim kan herrangskik om die effekte van ’n antibiotika te ontduik.

Bakterieë het verskeie maniere om weerstand te ontwikkel. Hulle kan muteer om te verhoed dat antibiotika hulle teiken, wat gedoen kan word deur die proteïene binne die sel waar antibiotika optree, te verander. Hulle kan ook gene verkry wat hulle help om antibiotika-vernietigende molekules, genoem ensieme, te produseer.

Al hierdie strategieë dra egter 'n koste vir weerstandbiedende bakterieë in. Die vervaardiging van weerstandsensieme verg baie energie. Gemodifiseerde proteïene kan ook nie so effektief presteer soos voorheen nie. Albei hierdie faktore belemmer bakterieë ernstig en laat hulle stadiger repliseer wanneer antibiotika nie teenwoordig is nie. Dit lei daartoe dat weerstandbiedende bakterieë die kompetisie teen ander bakterieë verloor om kosbare voedingstowwe en hulpbronne, wat hul voortbestaan ​​bedreig.

Die koste van antibiotika weerstand. Krediet: Célia Souque

Maar weerstandbiedende bakterieë het 'n manier gevind om weerstand teen antibiotika te word terwyl die koste daaraan verbonde beperk word. My onlangse studie het getoon hoe een so 'n meganisme, wat iets insluit wat bekend staan ​​as 'n integron, bakterieë 'n ongelooflike potensiaal bied om hoë vlakke van weerstand te verkry terwyl dit die energiekoste daarvan verminder. Dit maak dit makliker vir antibiotika-weerstandige bakterieë om te oorleef—en floreer.

Integrone is stukkies DNA, uniek aan bakterieë, wat bakterieë in staat stel om gene wat hulle van ander weerstandbiedende bakterieë verkry, op te stel. Hierdie weerstandsgene word een na die ander in die bakteriegenoom gerangskik en vorm "skikkings". Die posisie van die gene in die skikking het 'n groot impak op die bakterieë se weerstandsvlakke.

Gene wat aan die begin van die skikking teenwoordig is, word sterk uitgedruk (wat beteken dat hulle aktief gebruik word) en bied hoë vlakke van weerstand. Gene aan die agterkant word stil gehou en kan teen lae koste bewaar word, wat hul impak op die bakterieë verminder.

Boonop kom integrone met 'n fantastiese truuk: 'n ensiem, genaamd integrase, wat bakterieë toelaat om gene in die skikking af te sny en te beweeg wanneer die bakterieë in gevaar is. Daar word vermoed dat die integrase bakterieë die vermoë bied om die volgorde van hul gene te "skuifel", sodat bakterieë hul weerstandsvlakke op aanvraag kan moduleer. Ons studie was die eerste om hierdie hipotese te toets.

Om te sien hoe nuttig integrone vir bakterieë kan wees, het ons pasgemaakte integrone in die laboratorium gebou wat 'n relevante weerstandsgeen in die laaste posisie bevat het. Sommige is gemaak om 'n wanfunksionele integrase-ensiem te hê, wat sou verhoed dat hulle hul gene kon rondskuif. Dit het ons in staat gestel om die impak van geen-skuifel op antibiotika weerstand te meet.

Ons het toe 'n benadering genaamd eksperimentele evolusie gebruik waar ons bakterieë uitgedaag het met toenemende dosisse antibiotika en waargeneem het hoe lank hulle oorleef het. Hierdie tegniek het ons in staat gestel om direk te meet hoe goed bakterieë is om weerstand te ontwikkel.

Ons het gewys dat die bakterieë wat hul gene kon skommel, langer oorleef en weerstand ontwikkel meer gereeld as dié wat nie kon nie. Dit wys hoe integrone bakterieë kan help om hoë vlakke van antibiotika weerstand te ontwikkel in reaksie op behandeling met antibiotika.

Interessant genoeg was hierdie skuifel dikwels gekoppel aan die verlies van die ander weerstandsgene wat in die bakterieë teenwoordig is. Deur gene rond te skuif om weerstand teen ons gekose antibiotika te word, het bakterieë van hul ander weerstandsgene in die proses verloor - en word weer vatbaar vir hierdie ander antibiotika.

Die resultate van ons studie verskaf potensiële strategieë om integrone en hul rol in die ontwikkeling van weerstand teen te werk. Byvoorbeeld, antibiotika kan gekombineer word met middels wat die ensiem integrase kan inhibeer om geen skuifel te verminder. Dwelms wat die bakterieë se "SOS-reaksie" stop - die bakterieë se laaste uitwegreaksie op antibiotika - sal ook integron-skuifel beperk. Sogenaamde "anti-evolusie"-middels, wat nie bakterieë direk doodmaak nie, maar help om die evolusie van weerstand te voorkom, is tans 'n aktiewe navorsingsgebied.

Nog 'n alternatief sou wees om die integron-skuifel te ontgin om die verlies van weerstandsgene te bevorder deur deur verskillende antibiotika te fiets. Dit sal die evolusie van bakterieë op 'n manier stuur wat hulle sensitief maak vir voorheen onbruikbare antibiotika.

Integrone het die eerste keer miljoene jare gelede ontwikkel. Maar nou het hulle gevind dat hulle 'n unieke geskikte meganisme is vir bakterieë om aan te pas by die gebruik van antibiotika deur mense, en weerstand teen hulle ontwikkel.

Alhoewel antibiotika elke jaar talle lewens red, moet dit ook versigtig gebruik word om die verdere verspreiding van antibiotika-weerstandige bakterieë en siektes te vermy. Om beter te verstaan ​​hoe bakterieë weerstand ontwikkel, sal ons in staat stel om te verbeter hoe ons ons huidige antibiotika gebruik, sowel as dié wat ons in die toekoms sal ontwikkel.

Hierdie artikel is hergepubliseer vanaf The Conversation onder 'n Creative Commons-lisensie. Lees die oorspronklike artikel.


Inhoud

Alle plante en diere, van eenvoudige lewensvorme tot mense, leef in noue assosiasie met mikrobiese organismes. [12] Verskeie vooruitgang het die persepsie van mikrobiome aangedryf, insluitend:

  • die vermoë om genomiese en geenuitdrukking-ontledings van enkelselle en van hele mikrobiese gemeenskappe in die dissiplines van metagenomika en metatranskriptomika uit te voer[13]
  • databasisse toeganklik vir navorsers oor verskeie dissiplines [13]
  • metodes van wiskundige analise geskik vir komplekse datastelle [13]

Bioloë het begin besef dat mikrobes 'n belangrike deel van 'n organisme se fenotipe uitmaak, ver buite die af en toe simbiotiese gevallestudie. [13]

Tipes mikrobe-gasheer verhoudings Wysig

Kommensalisme, 'n konsep wat ontwikkel is deur Pierre-Joseph van Beneden (1809–1894), 'n Belgiese professor aan die Universiteit van Leuven gedurende die negentiende eeu [14] is sentraal tot die mikrobioom, waar mikrobiota 'n gasheer koloniseer in 'n nie-skadelike naasbestaan. Die verhouding met hul gasheer word mutualisties genoem wanneer organismes take verrig wat bekend is dat dit nuttig is vir die gasheer, [15] : 700 [16] parasities, wanneer dit nadelig vir die gasheer is. Ander skrywers definieer 'n situasie as mutualisties waar beide voordeel, en kommensaal, waar die onaangeraakte gasheer die simbion bevoordeel. [17] 'n Voedingstofuitruiling kan tweerigting of eenrigting wees, kan konteksafhanklik wees en kan op verskillende maniere plaasvind. [17] Mikrobiota wat na verwagting teenwoordig sal wees, en wat onder normale omstandighede nie siekte veroorsaak nie, word geag normale flora of normale mikrobiota [15] normale flora kan nie net skadeloos wees nie, maar kan beskermend vir die gasheer wees. [18]

Verkryging en verandering Wysig

Die aanvanklike verkryging van mikrobiota by diere van soogdiere tot mariene sponse is by geboorte, en kan selfs deur die kiemsellyn plaasvind. By plante kan die koloniseringsproses ondergronds in die wortelsone, rondom die ontkiemende saad, die spermosfeer geïnisieer word, of uit die bogrondse dele, die filosfeer en die blomsone of antosfeer ontstaan. [19] Die stabiliteit van die risosfeer-mikrobiota oor generasies hang af van die planttipe, maar selfs meer van die grondsamestelling, dit wil sê lewende en nie-lewende omgewing. [20] Klinies kan nuwe mikrobiota verkry word deur fekale mikrobiota-oorplanting om infeksies soos chroniese C. moeilikheid infeksie. [21]

Mense wysig

Die menslike mikrobiota sluit bakterieë, swamme, archaea en virusse in. Mikrodiere wat op die menslike liggaam leef, word uitgesluit. Die menslike mikrobioom verwys na hul genome. [15]

Mense word deur baie mikroörganismes gekoloniseer, die tradisionele skatting was dat mense met tien keer meer nie-menslike selle leef as menslike selle meer onlangse skattings het dit verlaag tot 3:1 en selfs tot ongeveer 1:1. [22] [23] [24] [25]

Trouens, dit is so klein dat daar ongeveer 100 biljoen mikrobiota op die menslike liggaam is, wat meer is as die hoeveelheid mense op aarde. [26]

Die Menslike Mikrobiome-projek het die genoom van die menslike mikrobiota op volgorde bepaal, en veral gefokus op die mikrobiota wat normaalweg die vel, mond, neus, spysverteringskanaal en vagina bewoon. [15] Dit het 'n mylpaal in 2012 bereik toe dit aanvanklike resultate gepubliseer het. [27]

Nie-menslike diere Wysig

  • Amfibieë het mikrobiota op hul vel. [28] Sommige spesies is in staat om 'n swam met die naam te dra Batrachochytrium dendrobatidis, wat in ander 'n dodelike infeksie Chytridiomycosis kan veroorsaak, afhangende van hul mikrobioom, weerstand teen patogeen kolonisasie of inhibeer hul groei met antimikrobiese vel peptiede. [29]
  • By soogdiere is herbivore soos beeste afhanklik van hul rumenmikrobioom om sellulose in proteïene, kortkettingvetsure en gasse om te skakel. Kultuurmetodes kan nie inligting verskaf oor alle mikroörganismes wat teenwoordig is nie. Vergelykende metagenomiese studies het die verrassende resultaat opgelewer dat individuele beeste aansienlik verskillende gemeenskapstrukture, voorspelde fenotipe en metaboliese potensiaal besit, [30] alhoewel hulle identiese diëte gevoer is, saam gehuisves is en blykbaar funksioneel identies was in hul benutting van plantselwande. hulpbronne. het die soogdier wat die meeste bestudeer is rakende hul mikrobiome geword. Die dermmikrobiota is bestudeer in verband met allergiese lugwegsiekte, vetsug, spysverteringsiektes en diabetes. Perinatale verskuiwing van mikrobiota deur lae dosis antibiotika kan langdurige effekte hê op toekomstige vatbaarheid vir allergiese lugwegsiekte. Die frekwensie van sekere subgroepe mikrobes is gekoppel aan die erns van die siekte. Die teenwoordigheid van spesifieke mikrobes vroeg in die postnatale lewe, lei toekomstige immuunresponse. [31] [32] In gnotobiotiese muise is gevind dat sekere dermbakterieë 'n spesifieke fenotipe na ontvanger-kiemvrye muise oordra, wat ophoping van kolonregulerende T-selle bevorder het, en stamme wat muisvet en kekale metabolietkonsentrasies gemoduleer het. [33] Hierdie kombinatoriese benadering maak 'n stelsel-vlak begrip van mikrobiese bydraes tot menslike biologie moontlik. [34] Maar ook ander slymvliesweefsels soos long en vagina is bestudeer in verband met siektes soos asma, allergie en vaginose. [35]
  • Insekte het hul eie mikrobiome. Blaarsnyermiere vorm byvoorbeeld groot ondergrondse kolonies wat elke jaar honderde kilogram blare oes en is nie in staat om die sellulose in die blare direk te verteer nie. Hulle handhaaf swamtuine as die kolonie se primêre voedselbron. Terwyl die swam self nie sellulose verteer nie, doen 'n mikrobiese gemeenskap wat 'n verskeidenheid bakterieë bevat dit. Ontleding van die mikrobiese populasie se genoom het baie gene aan die lig gebring met 'n rol in sellulosevertering. Hierdie mikrobioom se voorspelde koolhidraatafbrekende ensiemprofiel is soortgelyk aan dié van die beespens, maar die spesiesamestelling is byna heeltemal anders. [36] Darmmikrobiota van die vrugtevlieg kan die manier waarop sy ingewande lyk, beïnvloed deur die tempo van epiteelvernuwing, sellulêre spasiëring en die samestelling van verskillende seltipes in die epiteel te beïnvloed. [37] Wanneer die mot Spodoptera exigua met baculovirus besmet is, word immuunverwante gene afgereguleer en die hoeveelheid van sy dermmikrobiota neem toe. [38] In die dipteran-derm, voel entero-endokriene selle die dermmikrobiota-afgeleide metaboliete en koördineer antibakteriese, meganiese en metaboliese vertakkings van die gasheerderm se ingebore immuunrespons op die kommensale mikrobiota. [39]
  • Visse het hul eie mikrobiome, insluitend die kortlewende spesie Nothobranchius furzeri (turkoois moordvis). Die oordrag van die dermmikrobiota van jong moordvisse na middeljarige moordvisse verleng die lewensduur van die middeljarige moordvis aansienlik. [40]

Plante wysig

Daar is onlangs ontdek dat die planmikrobioom van die saad afkomstig is. [42] Mikro-organismes wat via saad oorgedra word, migreer na die ontwikkelende saailing op 'n spesifieke roete waarin sekere gemeenskappe na die blare en ander na die wortels beweeg. [42] In the diagram on the right, microbiota colonizing the rhizosphere, entering the roots and colonizing the next tuber generation via the stolons, are visualized with a red color. Bacteria present in the mother tuber, passing through the stolons and migrating into the plant as well as into the next generation of tubers are shown in blue. [41]

  • The soil is the main reservoir for bacteria that colonize potato tubers
  • Bacteria are recruited from the soil more or less independent of the potato variety
  • Bacteria might colonize the tubers predominantly from the inside of plants via the stolon
  • The bacterial microbiota of potato tubers consists of bacteria transmitted from one tuber generation to the next and bacteria recruited from the soil colonize potato plants via the root. [41]

Plants are attractive hosts for microorganisms since they provide a variety of nutrients. Microorganisms on plants can be epiphytes (found on the plants) or endophytes (found inside plant tissue). [43] [44] Oomycetes and fungi have, through convergent evolution, developed similar morphology and occupy similar ecological niches. They develop hyphae, threadlike structures that penetrate the host cell. In mutualistic situations the plant often exchanges hexose sugars for inorganic phosphate from the fungal symbiont. It is speculated that such very ancient associations have aided plants when they first colonized land. [17] [45] Plant-growth promoting bacteria (PGPB) provide the plant with essential services such as nitrogen fixation, solubilization of minerals such as phosphorus, synthesis of plant hormones, direct enhancement of mineral uptake, and protection from pathogens. [46] [47] PGPBs may protect plants from pathogens by competing with the pathogen for an ecological niche or a substrate, producing inhibitory allelochemicals, or inducing systemic resistance in host plants to the pathogen [19]

The symbiotic relationship between a host and its microbiota is under laboratory research for how it may shape the immune system of mammals. [48] [49] In many animals, the immune system and microbiota may engage in "cross-talk" by exchanging chemical signals, which may enable the microbiota to influence immune reactivity and targeting. [50] Bacteria can be transferred from mother to child through direct contact and after birth. [51] As the infant microbiome is established, commensal bacteria quickly populate the gut, prompting a range of immune responses and "programming" the immune system with long-lasting effects. [50] The bacteria are able to stimulate lymphoid tissue associated with the gut mucosa, which enables the tissue to produce antibodies for pathogens that may enter the gut. [50]

The human microbiome may play a role in the activation of toll-like receptors in the intestines, a type of pattern recognition receptor host cells use to recognize dangers and repair damage. Pathogens can influence this coexistence leading to immune dysregulation including and susceptibility to diseases, mechanisms of inflammation, immune tolerance, and autoimmune diseases. [52] [53]

Organisms evolve within ecosystems so that the change of one organism affects the change of others. The hologenome theory of evolution proposes that an object of natural selection is not the individual organism, but the organism together with its associated organisms, including its microbial communities.

Coral reefs. The hologenome theory originated in studies on coral reefs. [54] Coral reefs are the largest structures created by living organisms, and contain abundant and highly complex microbial communities. Over the past several decades, major declines in coral populations have occurred. Climate change, water pollution and over-fishing are three stress factors that have been described as leading to disease susceptibility. Over twenty different coral diseases have been described, but of these, only a handful have had their causative agents isolated and characterized. Coral bleaching is the most serious of these diseases. In the Mediterranean Sea, the bleaching of Oculina patagonica was first described in 1994 and shortly determined to be due to infection by Vibrio shiloi. From 1994 to 2002, bacterial bleaching of O. patagonica occurred every summer in the eastern Mediterranean. Surprisingly, however, after 2003, O. patagonica in the eastern Mediterranean has been resistant to V. shiloi infection, although other diseases still cause bleaching. The surprise stems from the knowledge that corals are long lived, with lifespans on the order of decades, [55] and do not have adaptive immune systems. [ aanhaling nodig ] Their innate immune systems do not produce antibodies, and they should seemingly not be able to respond to new challenges except over evolutionary time scales. [ aanhaling nodig ]

The puzzle of how corals managed to acquire resistance to a specific pathogen led to a 2007 proposal, that a dynamic relationship exists between corals and their symbiotic microbial communities. It is thought that by altering its composition, the holobiont can adapt to changing environmental conditions far more rapidly than by genetic mutation and selection alone. Extrapolating this hypothesis to other organisms, including higher plants and animals, led to the proposal of the hologenome theory of evolution. [54]

As of 2007 [update] the hologenome theory was still being debated. [56] A major criticism has been the claim that V. shiloi was misidentified as the causative agent of coral bleaching, and that its presence in bleached O. patagonica was simply that of opportunistic colonization. [57] If this is true, the basic observation leading to the theory would be invalid. The theory has gained significant popularity as a way of explaining rapid changes in adaptation that cannot otherwise be explained by traditional mechanisms of natural selection. Within the hologenome theory, the holobiont has not only become the principal unit of natural selection but also the result of other step of integration that it is also observed at the cell (symbiogenesis, endosymbiosis) and genomic levels. [8]

Targeted amplicon sequencing Edit

Targeted amplicon sequencing relies on having some expectations about the composition of the community that is being studied. In target amplicon sequencing a phylogenetically informative marker is targeted for sequencing. Such a marker should be present in ideally all the expected organisms. It should also evolve in such a way that it is conserved enough that primers can target genes from a wide range of organisms while evolving quickly enough to allow for finer resolution at the taxonomic level. A common marker for human microbiome studies is the gene for bacterial 16S rRNA (d.w.s. "16S rDNA", the sequence of DNA which encodes the ribosomal RNA molecule). [58] Since ribosomes are present in all living organisms, using 16S rDNA allows for DNA to be amplified from many more organisms than if another marker were used. The 16S rDNA gene contains both slowly evolving regions and fast evolving regions the former can be used to design broad primers while the latter allow for finer taxonomic distinction. However, species-level resolution is not typically possible using the 16S rDNA. Primer selection is an important step, as anything that cannot be targeted by the primer will not be amplified and thus will not be detected. Different sets of primers have been shown to amplify different taxonomic groups due to sequence variation.

Targeted studies of eukaryotic and viral communities are limited [59] and subject to the challenge of excluding host DNA from amplification and the reduced eukaryotic and viral biomass in the human microbiome. [60]

After the amplicons are sequenced, molecular phylogenetic methods are used to infer the composition of the microbial community. This is done by clustering the amplicons into operational taxonomic units (OTUs) and inferring phylogenetic relationships between the sequences. Due to the complexity of the data, distance measures such as UniFrac distances are usually defined between microbiome samples, and downstream multivariate methods are carried out on the distance matrices. An important point is that the scale of data is extensive, and further approaches must be taken to identify patterns from the available information. Tools used to analyze the data include VAMPS, [61] QIIME [62] and mothur. [63]

Metagenomic sequencing Edit

Metagenomics is also used extensively for studying microbial communities. [64] [65] [66] In metagenomic sequencing, DNA is recovered directly from environmental samples in an untargeted manner with the goal of obtaining an unbiased sample from all genes of all members of the community. Recent studies use shotgun Sanger sequencing or pyrosequencing to recover the sequences of the reads. [67] The reads can then be assembled into contigs. To determine the phylogenetic identity of a sequence, it is compared to available full genome sequences using methods such as BLAST. One drawback of this approach is that many members of microbial communities do not have a representative sequenced genome, but this applies to 16S rRNA amplicon sequencing as well and is a fundamental problem. [58] With shotgun sequencing, it can be resolved by having a high coverage (50-100x) of the unknown genome, effectively doing a de novo genome assembly. As soon as there is a complete genome of an unknown organism available it can be compared phylogenetically and the organism put into its place in the tree of life, by creating new taxa. An emerging approach is to combine shotgun sequencing with proximity-ligation data (Hi-C) to assemble complete microbial genomes without culturing. [68]

Despite the fact that metagenomics is limited by the availability of reference sequences, one significant advantage of metagenomics over targeted amplicon sequencing is that metagenomics data can elucidate the functional potential of the community DNA. [69] [70] Targeted gene surveys cannot do this as they only reveal the phylogenetic relationship between the same gene from different organisms. Functional analysis is done by comparing the recovered sequences to databases of metagenomic annotations such as KEGG. The metabolic pathways that these genes are involved in can then be predicted with tools such as MG-RAST, [71] CAMERA [72] and IMG/M. [73]

RNA and protein-based approaches Edit

Metatranscriptomics studies have been performed to study the gene expression of microbial communities through methods such as the pyrosequencing of extracted RNA. [74] Structure based studies have also identified non-coding RNAs (ncRNAs) such as ribozymes from microbiota. [75] Metaproteomics is an approach that studies the proteins expressed by microbiota, giving insight into its functional potential. [76]

The Human Microbiome Project launched in 2008 was a United States National Institutes of Health initiative to identify and characterize microorganisms found in both healthy and diseased humans. [77] The five-year project, best characterized as a feasibility study with a budget of $115 million, tested how changes in the human microbiome are associated with human health or disease. [77]

The Earth Microbiome Project (EMP) is an initiative to collect natural samples and analyze the microbial community around the globe. Microbes are highly abundant, diverse and have an important role in the ecological system. Yet as of 2010 [update] , it was estimated that the total global environmental DNA sequencing effort had produced less than 1 percent of the total DNA found in a liter of seawater or a gram of soil, [78] and the specific interactions between microbes are largely unknown. The EMP aims to process as many as 200,000 samples in different biomes, generating a complete database of microbes on earth to characterize environments and ecosystems by microbial composition and interaction. Using these data, new ecological and evolutionary theories can be proposed and tested. [79]

The gut microbiota is very important for the host health because it play role in degradation of non- digestible polysaccharides (fermentation of resistant starch, oligosaccharides, inulin) strengthening gut integrity or shaping the intestinal epithelium, harvesting energy, protecting against pathogens, and regulating host immunity. [80] [81]

Several studies showed that the gut bacterial composition in diabetic patients became altered with increased levels of Lactobacillus gasseri, Streptococcus mutans and Clostridiales members, with decrease in butyrate-producing bacteria such as Roseburia intestinalis en Faecalibacterium prausnitzii [82] [83] . This alteration is due to many factors such as antibiotic abuse, diet, and age.

The decrease in butyrate production is associated with defect in intestinal permeability, this defect lead to the case of endotoxemia, which is the increased level of circulating Lipopolysaccharides from gram negative bacterial cells wall. It is found that endotoxemia has association with development of insulin resistance. [82]

In addition that butyrate production affects serotonin level. [82] Elevated serotonin level has contribution in obesity, which is known to be a risk factor for development of diabetes.

Microbiota can be transplanted in the human body for medical purposes. [84]

The colonization of the human gut microbiota may start already before birth. [85] There are multiple factors in the environment that affects the development of the microbiota with birthmode being one of the most impactful. [86]

Another factor that has been observed to cause huge changes in the gut microbiota, particularly in children, is the use of antibiotics, associating with health issues such as higher BMI, [87] [88] and further an increased risk towards metabolic diseases such as obesity. [89] In infants it was observed that amoxicillin and macrolides cause significant shifts in the gut microbiota characterized by a change in the bacterial classes Bifidobacteria, Enterobacteria and Clostridia. [90] A single course of antibiotics in adults causes changes in both the bacterial and fungal microbiota, with even more persistent changes in the fungal communities. [91] The bacteria and fungi live together in the gut and there is most likely a competition for nutrient sources present. [92] [93] Seelbinder et al. found that commensal bacteria in the gut regulate the growth and pathogenicity of Candida albicans by their metabolites, particularly by propionate, acetic acid and 5-dodecenoate. [94] Candida has previously been associated with IBD [95] and further it has been observed to be increased in non-responders to a biological drug, infliximab, given to IBD patients suffering from severe IBD. [96] Propionate and acetic acid are both short-chain fatty acids (SCFAs) that have been observed to be beneficial to gut microbiota health. [97] [98] [99] When antibiotics affect the growth of bacteria in the gut, there might be an overgrowth of certain fungi, which might be pathogenic when not regulated. [100]

Microbial DNA inhabiting a person's human body can uniquely identify the person. A person's privacy may be compromised if the person anonymously donated microbe DNA data. Their medical condition and identity could be revealed. [101] [102] [103]


Turning bacteria against themselves

BEELD: The Streptococcus pyogenes toxin SPN (shown in purple) is inhibited by the antitoxin IFS (left, shown in orange). IFS blocks the active site of SPN and prevents NAD+ from binding. sien meer

Credit: Image provided by Craig L. Smith

Bacteria often attack with toxins designed to hijack or even kill host cells. To avoid self-destruction, bacteria have ways of protecting themselves from their own toxins.

Now, researchers at Washington University School of Medicine in St. Louis have described one of these protective mechanisms, potentially paving the way for new classes of antibiotics that cause the bacteria's toxins to turn on themselves.

Scientists determined the structures of a toxin and its antitoxin in Streptococcus pyogenes , common bacteria that cause infections ranging from strep throat to life-threatening conditions like rheumatic fever. In Strep, the antitoxin is bound to the toxin in a way that keeps the toxin inactive.

"Strep has to express this antidote, so to speak," says Craig L. Smith, PhD, a postdoctoral researcher and first author on the paper that appears Feb. 9 in the journal Structure . "If there were no antitoxin, the bacteria would kill itself."

With that in mind, Smith and colleagues may have found a way to make the antitoxin inactive. They discovered that when the antitoxin is not bound, it changes shape.

"That's the Achilles' heel that we would like to exploit," says Thomas E. Ellenberger, DVM, PhD, the Raymond H. Wittcoff Professor and head of the Department of Biochemistry and Molecular Biophysics at the School of Medicine. "A drug that would stabilize the inactive form of the immunity factor would liberate the toxin in the bacteria."

In this case, the toxin is known as Streptococcus pyogenes beta-NAD+ glycohydrolase, or SPN. Last year, coauthor Michael G. Caparon, PhD, professor of molecular microbiology, and his colleagues in the Center for Women's Infectious Disease Research showed that SPN's toxicity stems from its ability to use up all of a cell's stores of NAD+, an essential component in powering cell metabolism. The antitoxin, known as the immunity factor for SPN, or IFS, works by blocking SPN's access to NAD+, protecting the bacteria's energy supply system.

With the structures determined, researchers can now test possible drugs that might force the antitoxin to remain unbound to the toxin, thereby leaving the toxin free to attack its own bacteria.

"The most important aspect of the structure is that it tells us a lot about how the antitoxin blocks the toxin activity and spares the bacterium," says Ellenberger.

Understanding how these bacteria cause disease in humans is important in drug design.

"There is a war going on between bacteria and their hosts," Smith says. "Bacteria secrete toxins and we have ways to counterattack through our immune systems and with the help of antibiotics. But, as bacteria develop antibiotic resistance, we need to develop new generations of antibiotics."

Many types of bacteria have evolved this toxin-antitoxin method of attacking host cells while protecting themselves. But today, there are no classes of drugs that take aim at the protective action of the bacteria's antitoxin molecules.

"Obviously they could evolve resistance once you target the antitoxin," Ellenberger says. "But this would be a new target. Understanding structures is a keystone of drug design."

Smith CL, Ghosh J, Elam JS, Pinkner JS, Hultgren SJ, Caparon MG, Ellenberger T. Structural basis of Streptococcus pyogenes immunity to its NAD+ glycohydrolase toxin. Structure . Feb. 9, 2011.

This work was supported by grants from the National Institutes of Health and the UNCF/Merck Science Initiative Postdoctoral Fellowship awarded to Craig L. Smith.

Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Vrywaring: AAAS en EurekAlert! is nie verantwoordelik vir die akkuraatheid van nuusvrystellings wat op EurekAlert geplaas is nie! deur bydraende instellings of vir die gebruik van enige inligting deur die EurekAlert-stelsel.


Rooting the bacterial tree of life

Scientists now better understand early bacterial evolution, thanks to new research featuring University of Queensland researchers.

Bacteria comprise a very diverse domain of single-celled organisms that are thought to have evolved from a common ancestor that lived more than three billion years ago.

Professor Phil Hugenholtz, from the Australian Centre for Ecogenomics in UQ's School of Chemistry and Molecular Biosciences, said the root of the bacterial tree, which would reveal the nature of the last common ancestor, is not agreed upon.

"There's great debate about the root of this bacterial tree of life and indeed whether bacterial evolution should even be described as a tree has been contested," Professor Hugenholtz said.

"This is in large part because genes are not just shared 'vertically' from parents to offspring, but also 'horizontally' between distant family members.

"We've all inherited certain traits from our parents, but imagine going to a family BBQ and suddenly inheriting your third cousin's red hair.

"As baffling as it sounds, that's exactly what happens in the bacterial world, as bacteria can frequently transfer and reconfigure genes horizontally across populations quite easily.

"This might be useful for bacteria but makes it challenging to reconstruct bacterial evolution."

For the bacterial world, many researchers have suggested throwing the 'tree of life' concept out the window and replacing it with a network that reflects horizontal movement of genes.

"However, by integrating vertical and horizontal gene transmission, we found that bacterial genes travel vertically most of the time - on average two-thirds of the time - suggesting that a tree is still an apt representation of bacterial evolution," Professor Hugenholtz said.

"The analysis also revealed that the root of the tree lies between two supergroups of bacteria, those with one cell membrane and those with two.

"Their common ancestor was already complex, predicted to have two membranes, the ability to swim, sense its environment, and defend itself against viruses."

The University of Bristol's Dr Tom Williams said this fact led to another big question.

"Given the common ancestor of all living bacteria already had two membranes, we now need to understand how did single-membrane cells evolve from double-membraned cells, and whether this occurred once or on multiple occasions," Dr Williams said.

"We believe that our approach to integrating vertical and horizontal gene transmission will answer these and many other open questions in evolutionary biology."

The research was a collaboration between UQ, the University of Bristol in the UK, Eötvös Loránd University in Hungary, and NIOZ in the Netherlands, and has been published in Science (DOI: 10.1126/science.abe5011).

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Dover and beyond

V: What was at stake in the Dover trial?

Miller: One of the things that the Dover trial brought to a head was the idea that the intelligent-design movement represented a genuine alternative, something very different from the creation-science movement that took hold in several states in the U.S. in the early 1980s. The advocates of intelligent design disavow any connection with creationism or creation science. They say their ideas are purely scientific and have nothing to do with religion.

In the trial, documents regarding the formation of the intelligent-design movement, the construction of the intelligent-design textbook that was recommended for use in the Dover schools, came to light. And it was very clear that intelligent design represented nothing more than an intentional effort to relabel creation science by taking all the same old arguments and putting a new label on them.

The second thing that was very much at stake in the trial was religious freedom. Religious freedom in this country is based on two great and essential principles. One is that the government shall not interfere with the free exercise of religion, and the other one is that the government shall not endorse or establish a religion. What the Dover board was doing very clearly, by their own statements, was trying to establish an official religion for the school district of Dover and trying to get science teachers to advance the Dover board's view of that religion.

Now, the members of the Dover board are perfectly entitled to hold all these religious views and to hold these views about intelligent design and evolution and everything else. But what they're not entitled to do, under our Constitution, is to use the force and power of the state to foist those ideas on young people. That would have been a very dangerous precedent if they'd been able to get away with it.

V: Was it wrong, in your view, for the Dover school board to try to get their ideas into the science classroom?

Miller: No idea should be inserted into the science classroom by force of law unless that idea can first win a place for itself in the scientific community. The real problem that happened in Dover was not intelligent design being a bad idea or anything else. The real problem was the use of a government agency to pick up an idea that science itself had rejected and to say, "We're going to put this idea in the science classroom regardless of its inability to win any following within science itself."

They did this for religious reasons. That's why they lost the case. But the general idea of not allowing science to work was at the heart of what was wrong about Dover.

"Not a single scientific society has made a statement or claim in support of intelligent design. In fact, quite the contrary."

V: So is this over? Are we beyond intelligent design yet?

Miller: I'd love to think that this battle is over. It's not. The war is going to go on. Intelligent design as anything resembling a scientific theory has been shown fundamentally to be intellectually bankrupt, and it's also been shown to be an idea that is religious in character, simply cloaked in the language of science. I think that came out of the trial at Dover. The evidence that was presented, and even the testimony from the other side, showed that beyond any shadow of a doubt.

But the people behind the intelligent-design movement will do what they've always done. They will move on, they'll change terms, they'll come up with a new label, and they'll continue to fight this fight against evolution and against scientific rationalism.

One of the legacies of the Dover trial is that the term intelligente ontwerp has almost become a kind of intellectual poison, and its advocates are running around saying, "No, no, no, no. We don't want to teach intelligent design in the schools." They'd better not, especially after the Dover trial. Instead, they say, "What we want to do is we want to teach critical analysis of evolution, or we want to teach the controversy surrounding evolution."

Ironically, when you look at what they actually would like to teach, it is simply the collection of anti-evolution arguments that were always part and parcel of intelligent design in the first place. So it is simply relabeling the intelligent design critique of evolution. And this idea of teaching the controversy is built upon a false premise, that there is a controversy within the scientific community on the issue of evolution. Well, there isn't. Evolution is, in fact, mainstream science.

V: Critics of Darwinism often say that evolution is a theory in crisis. Hoe sien jy dit?

Miller: Evolutionary theory has never been more active in terms of an area of inquiry and an area of scholarship than it is right now. Evolution as an idea has never been more useful than it is right now, because we use evolution everyday to interpret genomes, to develop drugs, to prolong the useful lifetime of antibiotics, to grow genetically modified crops—all these things have components of evolution in them.

If you look at the major scientific societies in the United States and around the world, not a single scientific society has made a statement or claim in support of intelligent design, in support of scientific creationism. In fact, quite the contrary. Every major scientific organization that I'm aware of that has taken a position on this issue has taken their position four-square in favor of evolution. So the notion that evolution is in some sort of crisis is just not true.

The intelligent-design movement, says Ken Miller, "is basically designed to bring the supernatural into science. And that kind of introduction would destroy both science and religion."

Interview conducted on April 19, 2007 by Joe McMaster, producer of "Judgment Day: Intelligent Design on Trial," and edited by Lauren Aguirre and Peter Tyson, executive editor and editor in chief of NOVA online


Kyk die video: TO JE ČINJENICA-evoluirajuća bakterija (Oktober 2022).