Characterization of the antibacterial activity of some antimicrobial-derived metabolites and their involvement in the development of antimicrobial resistance in bacteria of animal origin

一些抗菌剂衍生代谢物的抗菌活性表征及其与动物源细菌抗菌素耐药性发展的关系

• 批准号: RGPIN-2022-04264
• 负责人: Rhouma, Mohamed
• 金额: $ 2.11万
• 依托单位: Université de Montréal
• 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=743398
• 关键词: Characterization; antibacterial; activity; some; antimicrobial

Often described as the "quintessential One Health issue," antimicrobial resistance (AMR) is a global concern that poses a serious threat to human, animal, and environmental health. How the livestock sector contributes to the spread of AMR continues to be studied, with results pointing to the misuse of antimicrobials in farm animals having an impact on the selection of drug-resistant bacteria. The phenotypic and molecular study of AMR in bacteria of animal origin is often based on assessing the link between antimicrobials (parent molecules) and the AMR pattern of these bacteria. It is still mostly unknown if antimicrobial metabolites - released after the biodegradation of parent molecules within the animal - are involved in the selection and development of AMR. My proposal therefore aims to characterize, for the first time in pigs, both the in vitro and in vivo antibacterial activity of the major metabolites derived from some medically important antimicrobials (MIAs) and to characterize the evolution of bacterial resistance to these compounds compared to their parent molecules. Bacterial susceptibility to the MIAs and their metabolites will be assessed using the broth microdilution method, and genotypic characterization of AMR bacteria will be performed mostly using the Polymerase Chain Reaction (PCR). A continuous fermentation model will be used to characterize the stability of antimicrobial metabolites in conditions mimicking those found in swine intestines. An experimental post-weaning diarrhea model will be used to characterize in vivo both the antibacterial activity and the selection of AMR bacteria following the oral administration of the major antimicrobial-derived metabolites or their parent molecules. The most innovative molecular methods (high throughput sequencing, whole genome sequencing, whole-metagenome shotgun sequencing, etc.) will be used in this research program. We anticipate that some antimicrobial-derived metabolites will be associated with significant antibacterial activity and are involved in the selection of AMR bacteria, while they persist longer in a pig's body than their parent molecules. My research program will generate new findings under real field conditions, will provide data on better controlling AMR spread through the food chain, will develop a proof of concept to define a microbiological withdrawal period for antimicrobials used in pigs, and will produce ground-breaking advances in the characterization of antimicrobial-derived metabolites and their persistence in the bodies of pigs. These contributions will be useful to researchers, veterinarians, and producers in Canada and around the world in our global effort to contend with the major public health threat that AMR poses. To help achieve these goals, I will ensure that Highly Qualified Personnel (HQP) are trained and that the program will expand to become an international reference laboratory specialized in the study of antimicrobial-derived metabolites.

抗微生物抗性（AMR）通常被描述为“典型的一个健康问题”，这是一个全球关注的关注点，对人，动物和环境健康构成了严重威胁。牲畜部门如何继续研究AMR的扩散，结果表明，在农场动物中滥用抗菌剂对耐药细菌的选择有影响。 AMR在动物起源细菌中的表型和分子研究通常是基于评估抗菌剂（父分子）与这些细菌的AMR模式之间的联系。仍然未知是否参与AMR的选择和发育，是否在动物内母体分子生物降解后释放抗菌代谢产物。因此，我的建议旨在在猪中首次表征主要代谢物的体外和体内抗菌活性，这些代谢产物来自一些医学上重要的抗微生物剂（MIA），并表征了与父母分子相比，细菌抗性的进化。细菌对MIA及其代谢产物的敏感性将使用肉汤微稀释法评估，并且将主要使用聚合酶链反应（PCR）进行AMR细菌的基因型表征。连续发酵模型将用于表征模仿猪肠中发现的抗菌代谢物的稳定性。在口服主要抗菌衍生的代谢物或其父分子后，将使用实验性断压后腹泻模型来表征体内抗菌活性和AMR细菌的选择。该研究计划将使用最具创新性的分子方法（高吞吐量测序，整个基因组测序，全元素shot弹枪测序等）。我们预计，某些抗菌衍生的代谢产物将与显着的抗菌活性有关，并参与选择AMR细菌的选择，而它们在猪体内的持续时间比母体分子更长。我的研究计划将在实际野外条件下产生新的发现，将提供有关更好地控制AMR通过食物链的数据，将开发概念验证，以定义猪使用的抗菌剂的微生物戒断期，并将在抗菌剂的代谢物及其在猪头中的持久性抗菌体的表征产生突破性的进步。这些贡献将对加拿大和世界各地的研究人员，兽医和生产商有用，以应对AMR构成的主要公共卫生威胁。为了帮助实现这些目标，我将确保对高素质的人员（HQP）进行培训，该计划将扩展到成为国际参考实验室，专门研究抗菌衍生的代谢物。