Optimal Ovodefensins

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Concern about the development of resistance to antibiotics has reached the public consciousness with predictions that we are heading for a dark age where our ability to fight infection is severely compromised. Although the indiscriminate medical prescribing of antibiotics is part of the problem, their extensive use in agriculture has very much been in the spotlight. The use of antibiotics to promote growth and prevent infections in farmed animals is widespread in much of the world. Although this practice is banned in Europe, antibiotics are still widely used to treat diseases, especially of the gastrointestinal tract, and total use in animals has risen as the scale of production has increased. The need for responsible use of antibiotics and stewardship of this precious resource is likely to lead to significant restrictions on agricultural use. This presents tough challenges for the poultry industry, where maintaining good gut health is critical to the efficient production of poultry meat. Poultry supply around one third of the world's animal protein and although 60 billion birds are reared worldwide each year, demand is fast accelerating as our population grows. A need therefore exists for alternatives to antibiotics to improve gut health and energy retention to sustain the efficiency of animal production, not least as we compete with animals for dietary resources such as grain. We have characterised a novel family of antimicrobial peptides from eggs which possess potent activity against a number of bacteria. These small peptides, which we called ovodefensins, have been synthesised inexpensively on a large scale by our industrial collaborators. When tested in animals and artificial gut models they have potent favourable effects on bacterial communities in the gut. For example, in a critical region of the lower gut there is an increase in favourable organisms such as Lactobacilli and less undigested food is present, which indicates that the gut is working well. Indeed growth of the chickens was improved by 6% over just 3 weeks by in-feed administration of an ovodefensin, which is comparable to the effect of growth-promoting antibiotics. We propose to understand how the ovodefensin peptides exert their effect by examining the gut tissue and contents from chickens that have been fed the peptides. We will look for changes in gut structure and gene expression, as well as differences in the metabolites and microbes in the gut contents that may be associated with the beneficial effects of ovodefensins on gut health and growth. We also want to understand how treatment in the early days of a chick's life influences the colonisation of the gut by bacteria and how this influences maturation and function of the gut in later life. In terms of the ovodefensin peptides themselves we have found a wide range of these molecules across the egg-laying birds and reptiles. Evolution, driven presumably by the bacteria the eggs are exposed to, has resulted in diverse ovodefensins with different amino acids sequences but also in number of amino acids between key amino acids that determine the shape of the molecule. We want to understand how the key features of the molecules dictate the ability to kill bacteria and promote growth to inform the design of ovodefensins with improved activity. We will take a structured approach using gallin, a potent ovodefensin, to alter key amino acids that effect the properties of the molecule that are thought to be important for its activity against bacteria. Ultimately we aim to use the knowledge gained to design optimised ovodefensins which will have improved activity against bacteria and show even more potent activity to improve gut health in chickens and reduce the need to use antibiotics. The project is founded on research funded by BBSRC and AB Vista and benefits from substantial contributions from our industrial partners, reflecting the value to industry of the proposed research.