Optimal Ovodefensins

最佳卵防御素

• 批准号: BB/M020738/1
• 负责人: Ian Dunn
• 金额: $ 47.31万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM020738%2F1
• 关键词: Optimal; Ovodefensins

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.

对抗生素耐药性发展的担忧已经引起了公众的关注，人们预测我们正在走向一个黑暗时代，我们抵抗感染的能力将受到严重损害。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备受关注。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区都很普遍。尽管这种做法在欧洲被禁止，但抗生素仍然广泛用于治疗疾病，特别是胃肠道疾病，并且随着生产规模的扩大，在动物中的总使用量也有所增加。 负责任地使用抗生素和管理这一宝贵资源的需要可能会导致对农业使用的重大限制。这给家禽业带来了严峻的挑战，保持良好的肠道健康对于禽肉的高效生产至关重要。家禽供应约三分之一的世界动物蛋白，尽管全世界每年饲养 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，尤其是当我们与动物争夺谷物等饮食资源时。 我们从鸡蛋中鉴定出一类新型抗菌肽，它们对多种细菌具有有效的活性。这些小肽，我们称之为卵防御素，是由我们的工业合作者大规模廉价合成的。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强大的有利影响。例如，在下肠道的关键区域，乳酸杆菌等有利生物体增加，未消化的食物减少，这表明肠道运转良好。事实上，通过饲料中施用卵防御素，鸡的生长在短短 3 周内就提高了 6%，这与促生长抗生素的效果相当。我们建议通过检查饲喂该肽的鸡的肠道组织和内容物来了解卵防御素肽如何发挥其作用。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物和微生物的差异，这些变化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，我们在产蛋鸟类和爬行动物中发现了多种此类分子。进化可能是由鸡蛋所接触的细菌驱动的，导致了多种不同的卵防御素，它们具有不同的氨基酸序列，而且关键氨基酸之间的氨基酸数量也决定了分子的形状。我们希望了解分子的关键特征如何决定其杀死细菌和促进生长的能力，以便为设计具有改进活性的卵防御素提供信息。我们将采用一种结构化方法，使用五倍子（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，其将提高抗细菌活性，并表现出更有效的活性，以改善鸡的肠道健康并减少使用抗生素的需要。该项目以 BBSRC 和 AB Vista 资助的研究为基础，并受益于我们工业合作伙伴的大量贡献，反映了拟议研究对工业的价值。