Munck, Christian

Bakterier som bliver udsat for antibiotika kan overleve ved at blive resistente. Det kan de enten opnå via chromosomale mutationer eller horisontal erhvervelse af resistensgener. Resistens i sygdomsfremkaldende bakterier er et omfattende problem som kan resulterer i en uvirksom behandling med en øget morbiditet og mortalitet som konsekvens. For effektivt at kunne imødegå en stigende udfordring fra resistente bakterier, er det nødvendigt at opnå en detaljeret forståelse af de mekanismer der fører til resistens. I mit PhD-forløb har jeg studeret to centrale aspekter ved resistensudvikling: (1) adaptivt resistens og (2) horisontalt erhvervet resistens.Ved at udsætte E. coli for enkel- og flerstof antibiotika og efterfølgende studere de geno- og fænotypiske responser, har jeg afdækket de evolutionære veje der fører til resistens i denne organisme. I modsætning til en generel forestilling om uafhængige responser, fandt jeg, at der er et stort overlap i de evolutionære responser som bl.a. manifesterer sig ved kollaterale ændringer i antibiotika overfølsomheden. Specifikt har jeg vist, at resistensudviklinger er stærkt nedsat overfor antibiotikakombinationer hvor responserne til komponentstofferne medfører kollateral sensitivitet. Mine resultater viser, at en detaljeret forståelse af resistensudvikling kan benyttes til rationelt at sammensætte antibiotikakombinationer, som er særligt velegnet til at forebygge resistensudvikling.I mit andet studium har jeg fokuseret på resistensudvikling via horisontal erhvervelse af resistensgener. Mere specifikt, har jeg fokuseret på generhvervelse fra ikke-humane miljøer. Studiet har undersøgt resistensgen-reservoirs i en række forskellige spildevandsrensningsanlæg samplet over en toårig periode. Jeg fandt, at selvom der var et omfattende og stabilt resistensgen-reservoir, var resistensgenerne fra spildevandsrensningsanlæg ikke delte med andre miljøer. Dette antyder, at der er en barrierer som forhindre omfattende genudveksling mellem bakterier fra forskellige miljøer.Bacteria can avoid extinction during antimicrobial exposure by becoming resistant. They achieve this either via adaptive mutations or horizontally acquired resistance genes. If resistance emerges in clinical relevant species, it can lead to treatment failure and ultimately result in increasing morbidity and mortality as well as an increase in the cost of treatment. Understanding how bacteria respond to antibiotic exposure gives the foundations for a rational approach to counteract antimicrobial resistance.In the work presented in this thesis, I explore the two fundamental sources of antimicrobial resistance: (1) adaptive mutations and (2) horizontal acquisition of resistance genes from antibiotic gene reservoirs.By studying the geno- and phenotypic changes of E. coli in response to single and drug-pair exposures, I uncover the evolutionary trajectories leading to adaptive resistance. I find, in contrast to a general assumption of independent responses, that there is a high degree of interactions between the evolutionary responses to the individual drugs, which is manifested in collateral changes in drug susceptibility. Specifically, I show that collateral sensitivity can be exploited to rationally design drug combinations that limit the evolution of antibiotic resistance due to counteracting evolutionary trajectories. My results highlight that an in-depth knowledge about the genetic responses to the individual antimicrobial compounds enables the prediction of responses to drug combinations.In the second study I focus on horizontal gene transfer as a way of achieving resistance. More specifically, I focus on gene acquisition from environmental reservoirs. The study investigates the resistance gene reservoirs in several wastewater treatment plants (WWTPs) sampled over a two years period. I find, that although the resistance gene reservoir is highly shared across different WWTPs, there is only a small overlap with resistance genes from other environments. This finding suggests, that there is a dissemination barrier preventing the spread of functional resistance genes across environmental niches

Online Research Database In Technology

Antibiotic Resistance:Adaptive Evolution &amp; Dissemination of Resistance Genes

http://orbit.dtu.dk/ws/files/102862913/Phd_afhandling..PDF

Antibiotic Resistance:Adaptive Evolution & Dissemination of Resistance Genes

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Online Research Database In Technology

Antibiotic Resistance:Adaptive Evolution &amp; Dissemination of Resistance Genes

Abstract

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Full text

Available Versions

Online Research Database In Technology

Antibiotic Resistance:Adaptive Evolution & Dissemination of Resistance Genes