Studying the role of persistence in the emergence of antibiotic resistance through experimental evolution

Etthel Windels
Aan de hand van evolutie-experimenten met bacteriën werd aangetoond dat persistentie het ontstaan van antibioticumresistentie stimuleert. Dit werd onderbouwd door wiskundige modellen en mechanistische experimenten.

Bacteriële persistentie: een nieuwe weg naar superbacteriën

In de context van de oprukkende antibioticumcrisis wordt de bestrijding van infecties steeds uitdagender. Paradoxaal genoeg heeft jarenlang overvloedig antibioticumgebruik onze bacteriële vijanden alleen maar sterker gemaakt. Resistentie is hun meest bekende verdedigingsstrategie, maar daarmee is niet alles gezegd. Haast alle bacteriële populaties bevatten een piepkleine fractie inactieve cellen die tijdelijk ongevoelig zijn voor antibiotica. Dat deze gespecialiseerde cellen dringend meer aandacht verdienen, blijkt nu uit het feit dat ze belangrijke voorlopers vormen van resistente bacteriën.

De ontdekking van antibiotica enkele decennia geleden leverde ons levensreddende middelen op in de strijd tegen infectieziektes. Dankzij de ongeëvenaarde effectiviteit waarmee ze bacteriën verdelgen, geloofden we jarenlang dat die strijd definitief gestreden was. Helaas is niets minder waar. Onder meer de opkomst van resistente bacteriën, die geen hinder ondervinden van het gebruikte antibioticum, tempert de aanvankelijke euforie. Hoewel de aanpak van antibioticumresistentie pas sinds kort op de beleidsagenda staat, doken de eerste problemen reeds op bij de start van het antibioticumtijdperk. Het fenomeen werd echter sterk in de hand gewerkt door het jarenlang overmatig gebruik en misbruik in de geneeskunde en de veehouderij. Het gevolg is een alarmerende opkomst van dodelijke ‘superbacteriën’ die we met geen enkel antibioticum kunnen bestrijden en die zich met een onvoorziene snelheid verspreiden. Door de afnemende werking van de bestaande medicatie beginnen we stilaan te beseffen dat banale infecties of simpele verwondingen opnieuw onze dood kunnen betekenen.

Maar het gevaar schuilt ook in een andere hoek. Het vaak beperkte succes van antibioticumbehandelingen bij chronische infecties heeft immers ook een veel minder bekende oorzaak, die als ‘persistentie’ bestempeld wordt. Hoewel medicatie vaak wel werkzaam is tegenover het overgrote deel van een bacteriële populatie, is een heel klein percentage van zogenaamde ‘persistorcellen’ toch in staat om aan de werking te ontsnappen en zo een volledige uitroeiing van de populatie te vermijden. Dat doen ze door tijdens de behandeling in een soort overlevingsmodus te gaan: hun metabole activiteit daalt aanzienlijk en ze vermenigvuldigen zich niet langer, ten voordele van een sterke tolerantie tegenover tal van antibiotica. Na het stopzetten van de kuur ontwaakt die kleine fractie persistorcellen en vermenigvuldigen ze zich, met hernieuwde symptomen tot gevolg. En alsof dat nog niet zorgwekkend genoeg is, toonde recent onderzoek aan dat frequente antibioticumbehandelingen het aantal persistorcellen in een bacteriële populatie kunnen doen toenemen.

Hoe kunnen we de huidige antibioticumcrisis opnieuw onder controle krijgen? We moeten goed beseffen dat antibiotica een verantwoord en oordeelkundig gebruik vereisen, willen we de effectiviteit ervan niet verder teniet doen. Inzicht in het ontstaan en de mechanismen van zowel resistentie als persistentie vormen dan ook een belangrijk vertrekpunt bij de keuze van een geschikte antibioticumbehandeling. De resultaten van dit eindwerk tonen aan dat persistentie een rol speelt in het ontstaan van resistentie en dus een nieuwe factor is waar antibioticumtherapieën in de toekomst rekening mee moeten houden.

Aan de hand van wiskundige modellen konden we reeds voorspellen dat er sneller resistentie zou ontstaan in een bacteriële populatie die meer persistorcellen bevat. Door antibioticumbehandelingen na te bootsen in het lab, toonden we aan dat die voorspellingen ook overeenkomen met de realiteit. De onderliggende verklaring voor dit fenomeen is tweevoudig. Enerzijds blijven persistorcellen vaak over na een antibioticumbehandeling en vormen ze zo een bron van resistente bacteriën. Anderzijds ontdekten we dat de SOS respons een extra link vormt tussen persistentie en resistentie. De SOS respons is een mechanisme dat het ontstaan van resistentie stimuleert en dat geactiveerd wordt wanneer het DNA van bacteriën beschadigd is, bijvoorbeeld door bepaalde antibiotica. In persistorcellen is de SOS respons actiever, waardoor ze meer kans maken om resistent te worden. Als we erin slagen om dit mechanisme te onderdrukken tijdens een antibioticumbehandeling, dan kunnen we hiermee het ontstaan van resistentie doen vertragen.

Ons onderzoek wijst persistentie dus aan als een nieuwe risicofactor in het ontstaan van antibioticumresistentie. Dit betekent dat persistentie een nog belangrijkere rol speelt in de huidige antibioticumcrisis dan aanvankelijk verwacht. Enige nuance is echter op zijn plaats. Voorlopig toonden we enkel een effect aan wanneer we bacteriën lieten groeien op een vaste voedingsbodem, een situatie die gelijkenissen vertoont met bepaalde chronische weefselinfecties. Verder onderzoek is nodig om te weten te komen of hetzelfde zich voordoet bij andere infectievormen.

Willen we ziekmakende bacteriën alsnog te slim af zijn, dan moeten we onze strategie dus grondig herzien. Het onderdrukken van persistentie moet hierin dringend een nieuw aandachtspunt vormen, niet alleen om chronische infecties te bestrijden, maar ook om het ontstaan van antibioticumresistentie af te remmen.

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Universiteit of Hogeschool
Master of science in de bio-ingenieurswetenschappen: cel- & gentechnologie
Publicatiejaar
2016
Promotor(en)
Jan Michiels
Kernwoorden
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