Combatting antimicrobial resistance in bovine mastitis through alternative non-antibiotic strategies

全球对牛奶的需求越来越大，因为它是一种营养丰富的天然食品，可以加工成许多不同的产品，供广大人口使用。2020年，牛奶占英国农业总产量的16.4%，按市场价格计算，牛奶价值44亿英镑，使英国成为世界第13大牛奶生产国。然而，由于抗微生物细菌感染奶牛的乳房，导致乳腺炎，这一重要的安全食品来源的供应受到威胁。乳腺炎是一种由微生物感染引起的乳房炎症，会影响牛奶的生产、质量和安全。它是最重要的地方性传染病，仍然是英国，加拿大和全球乳制品行业的主要挑战。乳腺炎有很高的患病率和发病率（约35例（英国）和19例（加拿大）/ 100/年）。此外，乳腺炎的临床管理具有挑战性，因为感染不仅涉及一种微生物，而且涉及多种微生物，使其难以诊断。导致乳腺炎的许多微生物不再对目前可用的抗生素治疗有反应，因为它们已经对这些抗生素产生耐药性，这一事实进一步加剧了这一情况。抗菌素耐药性与抗菌素使用密切相关，是对人类健康的重大全球威胁，据预测，它每年可能导致500万人死亡。从公共卫生的角度来看，奶牛的抗菌素耐药性可能危害人类健康，因为乳腺炎抗菌素耐药性病原体可能通过食用受感染的乳制品、在环境中处理乳制品时间接传播给人类，或通过与动物直接接触传播给人类。乳腺炎感染中的抗菌素耐药性细菌不仅对乳腺炎的临床管理构成挑战，而且对英国、加拿大和全球粮食安全构成威胁。处理后牛奶中的抗菌素残留也会造成处理期间丢弃的牛奶和处理后停药期间的牛奶损失。因此，迫切需要替代的、新的无抗生素治疗来对抗奶牛的抗菌素耐药性。因此，至关重要的是，我们加强研究，以提高我们对与乳腺炎分离株的生存和持久性有关的AMR决定因素的患病率的认识。这对于疾病的临床管理和开发替代无抗生素治疗至关重要。在过去的8年中，我们已经开发和表征了许多新颖有效的抗菌肽（amp）。因此，在本项目中，我们将评估这些新的无毒amp的活性，这些amp已被证明具有抗多种耐药（MDR）乳腺炎细菌的抗菌和抗生物膜活性。此外，我们将评估使用这些AMP制剂治疗临床乳腺炎如何影响AMR细菌在奶牛中的存在和传播。我们还将研究“正常”/健康牛奶与乳腺炎牛奶的微生物和抗菌药物耐药性组成，并评估抗菌药物治疗后的变化。这个项目是及时的，因为乳腺炎已被英国政府强调为重点关注。减少奶牛群乳腺炎的经济、环境和社会需求需要有效的、有针对性的治疗方法来改善管理，这个拟议项目的产出将有助于英国政府实现抗击抗生素耐药性挑战的目标。

Milk is increasingly in global demand because it is a nutritious natural food that can be processed into many different products accessible to a wide population, It accounted for 16.4% of total agricultural output in the UK in 2020 and was worth £4.4bn in market prices making the UK the thirteenth-largest milk producer in the world. However, this supply of this important safe food source is under threat due to antimicrobial resistant bacteria that infect the udder of dairy cows, causing mastitis. Mastitis is an inflammation of the udder caused by microbial infections that compromise milk production, quality and safety. It is the foremost endemic infectious disease which remains a major challenge to the UK, Canada and global dairy industries. Mastitis has a high prevalence and incidence (~35 (UK) and 19 (Canada) cases /per 100/year). Furthermore, clinical management of mastitis is challenging because not just one but the multiple microorganisms are involved in the infection, making it difficult to diagnose. This is further compounded by the fact that many of these microorganisms that cause mastitis no longer respond to current available antibiotic treatments as they have become resistant to these antibiotics. Antimicrobial resistance (AMR) is closely linked to antimicrobial use and is a major global threat to human health, with projections that it could lead to 5 million human deaths per year. From a public health perspective, AMR in dairy cattle can jeopardize human health, due to the potential spread of mastitic AMR pathogens to humans via consumption of infected dairy products, indirectly when dairy products are disposed of in the environment, or through direct contact with the animals.AMR bacteria in mastitis infections not only poses a challenge for clinical management of mastitis but poses a threat to UK, Canada and global food security. Antimicrobial residues in milk after treatment also contribute to losses from milk discarded during treatment and from withdrawal period post-treatment. Therefore, alternate, new antibiotic-free treatments are urgently needed to fight AMR in dairy cattle. Consequently, it is paramount that we intensify research to enhance our knowledge about the prevalence of AMR determinants involved in the survival and persistence of mastitis isolates. This is vital for clinical management of the disease and for the development of alternative antibiotic-free treatments.Over the past 8 years, we have developed and characterised many novel and efficacious antimicrobial peptides (AMPs). Consequently, in this project, we will evaluate the activity of these new, non-toxic AMPs, which have proven antimicrobial and antibiofilm activity against species of multi-drug resistant (MDR) mastitis bacteria.Additionally, we will assess how treatment of clinical mastitis with these AMP formulations influence the presence and spread of AMR bacteria in dairy cattle. We will also investigate what the microbial and AMR composition of 'normal'/healthy milk versus mastitis milk and evaluate how this changes post treatment with AMPs.This project is timely as mastitis has been highlighted as a key focus by UK Government. The economic, environmental, and social needs to reduce mastitis in dairy herds require effective, targeted treatments for improved management, and the output from this proposed project will facilitate UK Government goal to combat the AMR challenge.