Optimal Ovodefensins

对抗生素耐药性发展的担忧已经进入公众意识，预测我们正在走向一个黑暗时代，我们对抗感染的能力严重受损。尽管滥用抗生素是问题的一部分，但抗生素在农业中的广泛使用一直是人们关注的焦点。使用抗生素来促进养殖动物的生长和预防感染在世界许多地方都很普遍。尽管这种做法在欧洲被禁止，但抗生素仍被广泛用于治疗疾病，特别是胃肠道疾病，随着生产规模的增加，动物的总使用量也在增加。 负责任地使用抗生素和管理这一宝贵资源的必要性可能会导致对农业使用的重大限制。这对家禽业提出了坚韧的挑战，保持良好的肠道健康对禽肉的高效生产至关重要。家禽提供了世界上大约三分之一的动物蛋白，尽管每年全世界饲养600亿只家禽，但随着人口的增长，需求正在迅速增长。因此，需要抗生素的替代品来改善肠道健康和能量保留，以维持动物生产的效率，尤其是因为我们与动物竞争粮食等膳食资源。 我们已经表征了一个新的家庭的抗菌肽从鸡蛋，具有强大的活性，对一些细菌。这些小肽，我们称之为卵防御素，已经由我们的工业合作者廉价地大规模合成。当在动物和人工肠道模型中进行测试时，它们对肠道中的细菌群落具有潜在的有利影响。例如，在下消化道的一个关键区域，有利的生物体如乳酸杆菌增加，未消化的食物减少，这表明肠道工作良好。事实上，通过在饲料中施用卵防御素，鸡的生长在短短3周内改善了6%，这与促进生长的抗生素的效果相当。我们建议了解如何卵防御素肽发挥其作用，通过检查肠道组织和内容物，从鸡已被喂食的肽。我们将寻找肠道结构和基因表达的变化，以及肠道内容物中代谢产物和微生物的差异，这些差异可能与卵防御素对肠道健康和生长的有益作用有关。我们还想了解在雏鸡生命早期的治疗如何影响细菌在肠道的定植，以及这如何影响后期肠道的成熟和功能。就卵防御素肽本身而言，我们已经在产卵的鸟类和爬行动物中发现了广泛的这些分子。进化，大概是由鸡蛋所接触的细菌驱动的，已经导致了具有不同氨基酸序列的多种卵防御素，而且在决定分子形状的关键氨基酸之间的氨基酸数量也不同。我们希望了解这些分子的关键特征如何决定杀死细菌和促进生长的能力，从而为卵防御素的设计提供信息。我们将采取一种结构化的方法，使用gallin，一种有效的卵防御素，来改变影响分子特性的关键氨基酸，这些特性被认为对其抗细菌活性很重要。最终，我们的目标是利用所获得的知识来设计优化的卵防御素，这些卵防御素将提高对细菌的活性，并显示出更有效的活性，以改善鸡的肠道健康并减少使用抗生素的需要。该项目建立在BBSRC和AB Vista资助的研究基础上，并受益于我们的工业合作伙伴的大量贡献，反映了拟议研究对工业的价值。

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.