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

点击翻译按钮获取中文摘要

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.