Mitigation of antimicrobial resistance in staphylococcal isolates from bovine milk

减轻牛奶中葡萄球菌分离物的抗菌药物耐药性

• 批准号: RGPIN-2022-03884
• 负责人: zhao, xin
• 金额: $ 2.84万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=743581
• 关键词: Mitigation; antimicrobial; resistance; staphylococcal; isolates

One of today's biggest world health challenges is bacteria that are resistant to the antibiotics used to treat infections. Animal agriculture is the largest user of antibiotics in Canada to prevent and treat diseases. In the dairy industry, one major use of antibiotics is for treating mastitis, caused mainly by pathogenic bacteria. Among them, staphylococci, including Staphylococcus aureus (S. aureus) (major pathogens) and coagulase-negative staphylococcus (CNS) (minor pathogens) are important. Treatment of S. aureus mastitis has been complicated by its ability to persist in tissues and evade the host immune response and by lack of effective vaccines. In addition, unusually frequent acquisition of antimicrobial resistance among staphylococci, especially methicillin resistance, could contribute to significantly low cure rates. We have been working on antibiotic resistance of milk S. aureus and CNS isolates for the last 10 years. This proposed research builds on our continuing efforts and successes and takes advantage of our established collaboration with scientists in various countries. We will perform the following: (1) to identify unique methicillin-resistant determinants and other antimicrobial resistance (AMR) genes in S. aureus and CNS from mastitic milk. The results will contribute to the surveillance of AMR in animals and to reveal new targets for intervention; (2) to uncover specific genetic mutations during the development of tolerance after cyclic exposure to high concentrations of antibiotics. Resistance is a primary determinant in the survival of bacteria under antibiotics. However, bacteria can also become recalcitrant to antibiotic treatment, without developing resistance, a phenomenon termed "tolerance". By studying genetic changes during the development of tolerance, we can understand how new resistance is developed; and (3) to develop novel antimicrobial peptides (AMPs) and peptide nucleic acids (PNAs) for eliminating intracellular S. aureus in bovine mammary epithelial cells. Both AMPs and PNAs are novel alternatives to traditional antibiotics to tackle the problem of bacterial multidrug resistance. The proposed research is highly original and innovative for solving the AMR problem in mastitis-causing bacteria. This proposed research will contribute to understanding mechanisms for the formation of bacterial AMRs and to reduce mastitis in dairy cows. In addition, this research may be relevant to human health because methicillin-resistant S. aureus and CNS from milk potentially pose a hazard to human health, both through horizontal transfer of resistance genes between staphylococcal species and through direct transmission of resistant pathogens between humans and animals. Therefore, this proposed research has potential economic benefits to dairy producers, health benefits to animal welfare and possibly to humans, and social benefits to policy making for dealing with the AMR problem as well as training highly qualified personnel.

当今世界最大的卫生挑战之一是细菌对用于治疗感染的抗生素具有耐药性。畜牧业是加拿大用于预防和治疗疾病的抗生素的最大使用者。在乳制品行业，抗生素的一个主要用途是治疗主要由致病菌引起的乳腺炎。其中，葡萄球菌，包括金黄色葡萄球菌（S. aureus）（主要病原体）和凝固酶阴性葡萄球菌（CNS）（次要病原体）是重要的。金黄色葡萄球菌乳腺炎的治疗由于其在组织中持续存在和逃避宿主免疫反应的能力以及缺乏有效的疫苗而变得复杂。此外，葡萄球菌异常频繁地获得抗微生物药物耐药性，特别是甲氧西林耐药性，可能导致治愈率显著降低。在过去的10年里，我们一直在研究牛奶金黄色葡萄球菌和CNS分离株的抗生素耐药性。这项拟议的研究建立在我们持续的努力和成功的基础上，并利用了我们与各国科学家建立的合作关系。我们将进行以下工作：(1)从乳乳中鉴定金黄色葡萄球菌和CNS中独特的甲氧西林耐药决定因素和其他抗微生物药物耐药性（AMR）基因。研究结果将有助于监测动物的抗菌素耐药性，并揭示新的干预目标；(2)揭示循环暴露于高浓度抗生素后耐受性发展过程中的特定基因突变。耐药性是抗生素作用下细菌存活的主要决定因素。然而，细菌也可能对抗生素治疗变得顽固，而不会产生耐药性，这种现象被称为“耐受性”。通过研究耐受性发展过程中的遗传变化，我们可以了解新的抗性是如何产生的；(3)开发新型抗菌肽（AMPs）和肽核酸（PNAs），用于杀灭牛乳腺上皮细胞内金黄色葡萄球菌。amp和PNAs都是解决细菌多药耐药问题的传统抗生素的新替代品。本研究对解决引起乳腺炎的细菌抗菌素耐药性问题具有高度的原创性和创新性。本研究将有助于了解细菌抗菌素耐药性的形成机制，减少奶牛的乳腺炎。此外，这项研究可能与人类健康有关，因为来自牛奶的耐甲氧西林金黄色葡萄球菌和CNS可能通过葡萄球菌物种之间的抗性基因水平转移和人类与动物之间的抗性病原体直接传播对人类健康构成潜在危害。因此，这项拟议的研究对乳制品生产者具有潜在的经济效益，对动物福利和可能对人类具有健康效益，对处理AMR问题的政策制定以及培养高素质人才具有社会效益。