Rapid assessment of phage for combating antimicrobial resistance in Enterobacter cloacae using a novel insect model

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Antibiotics, drugs that can be used to treat and prevent bacterial infection, have revolutionized our ability to treat infectious disease and prevent infection during surgery. Unfortunately bacteria can become resistant to antibiotics by evolving. They can undergo genetic changes that enable them to tolerate or degrade antibiotics. We believe that there is a need to consider a whole raft of innovative solutions to resistance. One important possible solution is to increase our use of "biological" solutions to treat infections, such as the bacteria-killing viruses known as bacteriophage. While bacteriophage remedies have their limitations, they can be combined with antibiotics in a way that can improve treatment efficacy and also help slow the rate of the evolution of resistance. Evolution experiments require time and potentially many different hosts. While phage has much unexploited potential, currently it is difficult and expensive demonstrate the effectiveness of these tools by doing evolution of resistance experiments with laboratory mammals. For this proposal, we have specifically developed an insect system to investigate the evolution of resistance to antibiotics in the bacterium Enterobacter cloacae. This species is particularly difficult to treat because of its naturally occurring resistance to many penicillin-based antibiotics. It is an important cause of bladder and kidney infections as well as infections associated with intensive care. Our insect model captures many of important aspects of infections in vertebrates but has the added benefits of being easy to manipulate, free of ethical oversight, and very cost effective. With this model we can vary antibiotic consumption, the presence of resistance plasmids and numerous important conditions that will allow us to mimic different real world scenarios with large numbers of individual hosts. We will use experimental evolution to assess a range of ways of deploying bacteriophages to slow the evolution of resistance. This will include the use of virus to specifically kill those bacteria carrying genetic elements that confer resistance to antibiotics. We will investigate how to best to deploy bacteriophage in combination with phage, and how best to use phage to combat different forms of resistance. We will also look at important factors that might affect the value of phage in resistance management, such as the diversity of the bacteria in the gut. With the insect experiments we can find out what happens in weeks or months, if we change a range of control measures. If we would do this in the real world, it would be harder, more expensive and potentially take years. Such an experimental system will never be perfect, but it will give us a good idea what will happen, cheaply and quickly.While the insect models cannot entirely solve the problem of antibiotic resistance, we believe that they could provide an important new tool. With it we can rapidly look at the effectiveness of a large range of possible resistance management options on a population scale, and pick out the best ones, which can later be tried out in hospitals or in animal health.