Linus Sandegren

• Medarbetarportalen vid Uppsala universitet (kräver inloggning)

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Dynamics of plasmid-borne antibiotic resistance

We study fundamental aspects of how resistance plasmids are maintained and disseminated between pathogenic bacteria and how they serve as platforms for evolution of antibiotic resistance. The main focus is to understand how factors such as stability, mobility, positive selection and fitness cost influence the evolutionary success of plasmids. The experimental systems used are based on clinically isolated multi-resistance plasmids encoding extended spectrum β-lactamases (ESBLs) in enteric bacteria (Escherichia coli and Klebsiella pneumoniae) that pose an increasing clinical problem by providing bacteria with resistance to the most used antibiotics today, β-lactams such as penicillins and cephalosporins.

Four main themes are of particular interest in these studies:

1. What impact do low levels of antibiotics have on spread, selection and maintenance of multi-resistance plasmids?
2. What plasmid factors cause a fitness-cost on the host cell and can the fitness-cost of plasmid carriage be alleviated by the bacterium in the absence of antibiotics?
3. How common are gene amplifications during treatment, how do they affect the efficacy of antibiotics and does the dynamics of gene amplification on plasmids accelerate evolution of new resistance?
4. How is resistance development and plasmid dynamics influenced by bacterial growth in biofilms compared to planktonic growth?

From these studies we gain new knowledge of how bacterial cells and plasmids co-evolve and how selection of new resistance can accelerate through gene amplification at different antibiotic concentrations. Such knowledge can be used to design antibiotic treatment regimens that limit selection of resistance and minimize the potential for new resistance to evolve.