PhD project: How antibiotics kill persistent infections

Project description

Persistent, chronic infections can be very hard to treat with antibiotics, and this is especially important in the context of antimicrobial resistance, where overuse of antibiotics can lead to resistant infections.

In chronic infections, the pathogenic bacteria are often found in densely-packed, surface-associated communities known as biofilms. Biofilms tend to be resistant to antibiotics, but the reasons for this remain unclear. Biofilms are also a very beautiful example of multicellular self-assembly in biology, since they grow into different 3D structures depending on conditions like nutrient availability and fluid flow. But we do not as yet understand how the 3D structure of a biofilm affects how easy it is to treat with antibiotics, and how likely it is to produce mutant bacteria that are resistant to antibiotics. 

In this project, we will investigate the link between the 3D spatial structure of a biofilm infection and how it responds to antibiotic treatment. The project has scope to be experimental, computational, or a combination of both. 

From an experimental perspective, we have techniques established in our lab to grow biofilms, measure their spatial structure using confocal microscopy, and find out how they are affected by antibiotic treatment. We are also starting to think about ways to measure the evolution of antibiotic resistance in biofilms. As well as measuring these things for biofilms on flat surfaces, we will also test out ways of perturbing biofilm spatial structure (eg by growing on different surfaces) and see how this affects the efficacy of antibiotic treatment. 

From a computational perspective, we have extensive experience in our group of simulating biofilm growth in "individual-based models" where each bacterium is represented as an object and we define rules for how the objects interact with each other. We are also now starting to work with larger-scale continuum models where we do not model individual bacteria but we can simulate coarse-grained 3D structure formation over large areas. In this project, we would implement antibiotics in either individual-based or continuum biofilm models, determine how different types of antibiotics affect biofilm structure and are affected by biofilm structure, and eventually also simulate the evolution of antibiotic resistance in biofilms.

This project is interesting because it combines the development of complex spatial structure in multicellular communities (a broad topic that is relevant not just to bacteria but also in cancer, organ development etc), with the clinically relevant topic of antibiotic response and resistance. This project would suit either a student who likes to perform experimental work, or one who is keen on computer simulations, or someone who wants to combine the two. Prior biological knowledge is not required.

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