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

牛奶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，因此全球对牛奶的需求越来越大，2020年，牛奶占英国农业总产量的16. 4%，市场价格为44亿英镑，使英国成为全球第13大牛奶生产国。然而，这种重要的安全食物来源的供应受到威胁，由于感染奶牛乳房的抗菌素耐药性细菌，导致乳腺炎。乳腺炎是一种由微生物感染引起的乳房炎症，会影响牛奶的产量、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。乳腺炎的患病率和发病率很高（约35例（英国）和19例（加拿大）/每100例/年）。此外，乳腺炎的临床管理是具有挑战性的，因为感染中涉及的不仅仅是一种微生物，而是多种微生物，使得难以诊断。导致乳腺炎的许多这些微生物不再对当前可用的抗生素治疗产生反应，因为它们已经对这些抗生素产生耐药性。抗菌素耐药性（AMR）与抗菌素的使用密切相关，是全球对人类健康的主要威胁，预计每年可能导致500万人死亡。从公共卫生的角度来看，由于乳腺炎AMR病原体可能通过食用受感染的乳制品、在环境中处置乳制品时间接传播或通过与动物直接接触而传播给人类，因此奶牛中的AMR可能危及人类健康。乳腺炎感染中的AMR细菌不仅对乳腺炎的临床管理构成挑战，而且对英国构成威胁，加拿大与全球粮食安全治疗后乳汁中的抗菌剂残留物也会导致治疗期间丢弃的乳汁和治疗后停药期的乳汁流失。因此，迫切需要替代的新的无抗生素治疗方法来对抗奶牛的AMR。因此，我们必须加强研究，以提高我们对乳腺炎分离株存活和持续存在所涉及的AMR决定因素的患病率的认识。这对于疾病的临床管理和替代无抗生素治疗的发展至关重要。在过去的8年里，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已被证明对多药耐药（MDR）乳腺炎细菌具有抗菌和抗菌膜活性。此外，我们将评估这些AMP制剂治疗临床乳腺炎如何影响奶牛中AMR细菌的存在和传播。我们还将研究“正常”/健康牛奶与乳腺炎牛奶的微生物和AMR组成，并评估AMP治疗后的变化。该项目是及时的，因为乳腺炎已被英国政府强调为重点。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，该拟议项目的产出将促进英国政府应对AMR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.