Cornell University, Ithaca, New York, USA.
Université Paris-Saclay, INRAE, UVSQ, Virologie et Immunologie Moléculaires, Jouy-en-Josas, Paris, France.
Appl Environ Microbiol. 2024 Aug 21;90(8):e0035424. doi: 10.1128/aem.00354-24. Epub 2024 Jul 16.
Infections caused by antimicrobial-resistant are the leading cause of death attributed to antimicrobial resistance (AMR) worldwide, and the known AMR mechanisms involve a range of functional proteins. Here, we employed a pan-genome wide association study (GWAS) approach on over 1,000 isolates from sick dogs collected across the US and Canada and identified a strong statistical association (empirical < 0.01) of AMR, involving a range of antibiotics to a group 1 capsular (CPS) gene cluster. This cluster included genes under relaxed selection pressure, had several loci missing, and had pseudogenes for other key loci. Furthermore, this cluster is widespread in and clinical isolates across multiple host species. Earlier studies demonstrated that the octameric CPS polysaccharide export protein Wza can transmit macrolide antibiotics into the periplasm. We suggest that the CPS in question, and its highly divergent Wza, functions as an antibiotic trap, preventing antimicrobial penetration. We also highlight the high diversity of lineages circulating in dogs across all regions studied, the overlap with human lineages, and regional prevalence of resistance to multiple antimicrobial classes.
Much of the human genomic epidemiology data available for mechanism discovery studies has been heavily biased toward shiga-toxin producing strains from humans and livestock. occupies many niches and produces a wide variety of other significant pathotypes, including some implicated in chronic disease. We hypothesized that since dogs tend to share similar strains with their owners and are treated with similar antibiotics, their pathogenic isolates will harbor unexplored AMR mechanisms of importance to humans as well as animals. By comparing over 1,000 genomes with antimicrobial susceptibility data from sick dogs across the US and Canada, we identified a strong multidrug resistance association with an operon that appears to have once conferred a type 1 capsule production system.
在全球范围内，由抗菌药物耐药性引起的感染是导致抗菌药物耐药性（AMR）死亡的主要原因，已知的 AMR 机制涉及一系列功能蛋白。在这里，我们对来自美国和加拿大各地患病犬的 1000 多个分离株进行了全基因组关联研究（GWAS），并确定了 AMR 的强烈统计学关联（经验 < 0.01），涉及一系列抗生素到一组 1 型荚膜（CPS）基因簇。该簇包括在选择压力下放松的基因，有几个缺失的基因座，并且有其他关键基因座的假基因。此外，该簇在 和 临床分离株中广泛存在于多种宿主物种中。早期的研究表明，八聚体 CPS 多糖外排蛋白 Wza 可以将大环内酯类抗生素输送到 周质。我们认为，所讨论的 CPS 及其高度分化的 Wza，充当抗生素陷阱，防止抗菌渗透。我们还强调了在所研究的所有地区的犬中循环的谱系的高度多样性、与人类谱系的重叠以及对多种抗菌类别的耐药性的区域性流行。
可用于 AMR 机制发现研究的人类基因组流行病学数据大部分严重偏向于来自人类和牲畜的产志贺毒素菌株。 占据许多小生境，并产生许多其他重要的病理型，包括一些与慢性疾病有关的病理型。我们假设，由于犬往往与它们的主人共享相似的菌株，并接受类似的抗生素治疗，因此它们的致病分离株将具有未被探索的 AMR 机制，这些机制对人类和动物都很重要。通过比较来自美国和加拿大各地患病犬的 1000 多个基因组和 药敏数据，我们确定了一个与似乎曾经赋予 1 型荚膜产生系统的操纵子强烈的多药耐药性关联。
