Bacteriophages (phages) are viruses that prey on bacteria. In the early 20th century they were widely used to treat dangerous bacterial infections, e.g., cholera, but their popularity was eclipsed by the rise of conventional molecular antibiotics like penicillin. However, the growth of antimicrobial resistance (the rapid evolution in bacteria of resistance to conventional antibiotics) is now driving a resurgence of interest in phages as effective antibacterial agents, with approximately 40 phage-based companies set up so far worldwide. Many of the antibacterial applications rely on binding phages to surfaces, e.g., food packaging, seed coatings, animal feed, catheters and wound dressings, and companies, including the project partner Fixed Phage Ltd, are actively researching how to do this in a way that retains maximum antibacterial activity. The aim of this proposal is to understand the basic science underlying this problem, and to apply this understanding to design and optimize these phage-coated surfaces.
For human infections, we have the benefit of detailed mathematical models that help us to stop these infections spreading. I want to be able to use these mathematical models to enhance the spreading of phage infections among bacteria, but there are several basic science questions that must be answered before this can be done. This proposal addresses three of these questions, which are also of direct relevance to understanding how bacteriophage-coated surfaces work:
1) How does phage infection affect bacterial swimming and vice versa? Many bacteria swim, and this can spread the phage infection further. This is analogous to the way human infections can be spread by long-distance air travel, but for bacteria, very little is known; even the simple question of whether bacteria stop swimming immediately after infection, or just before they die some minutes later, remains open. Understanding this difference is important for mathematically modeling phage infections, including on antibacterial surfaces, and will help to determine important design parameters such as the density of phage coverage needed to ensure the infection spreads through the whole bacterial population.
2) How are the phages distributed and oriented on the surface? Phages inject DNA into bacteria through tube-like tail fibres. To be effective these fibres must contact the bacteria, but phages probably bind in random orientations, which will limit their activity. Similarly, the most effective phage-coated surfaces will have a uniform distribution of phages across the surface, but a widespread phenomenon in drying droplets, called the 'coffee-ring effect' may cause the bacteriophages to clump together. This is particularly significant because bacteria attached to surfaces can grow and aggregate into highly resistant colonies known as biofilms; a phage-poor region of the surface presents an ideal opportunity to do this. This leads to:
3) How does bacterial aggregation affect infection dynamics? Dense bacterial aggregates present a physical challenge for bacteriophage treatment (the phages can't get in), but they can also act as phage reservoirs. Understanding the competitive dynamics between bacterial aggregation and phage infection is a key challenge, and modelling this will be important for a wide range of applications. This includes using phages to treat human infections, where resistant biofilms pose a huge challenge.
I will address these questions with experiments and mathematical modelling, looking for fundamental physical principles that can be applied to optimize antimicrobial surfaces, and design new devices for novel applications. With the aim of developing clinical applications, I will also test how these principles carry over into a system containing bacteriophages, bacteria and cultured human cells, which is a model for bacterial infections.
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