摘要
      质粒是细菌抗生素耐药性的主要载体，但对质粒抗生素耐药性基因（ARG）携带相关因素的了解有限。我们策划 > 14000个公开可用的质粒基因组和相关元数据。排除重复质粒和重复质粒；在可能的情况下，对样本元数据进行外部验证（BacDive数据库）。使用广义加性模型（GAM），我们评估了12种生物/非生物因素（如质粒遗传因素、分离来源、收集日期）对ARG携带的影响，建模为二元结果。为10种主要的ARG类型构建了单独的GAM。多变量分析表明，质粒ARG随时间（采集年份）、分离来源（人/牲畜）和宿主细菌分类群的携带模式与抗生素选择压力一致，抗生素选择压力是质粒介导的抗生素耐药性的驱动因素。只有0.42%的牲畜质粒携带碳青霉烯抗性（相比之下，12%的人类质粒）；相反，四环素耐药性在牲畜和人类质粒中富集，反映了已知的处方实践。使用ARG类型获取的时间线（由文献综述确定）解释结果产生了额外的新颖见解。最近获得的ARG类型（如粘菌素和碳青霉烯）在分析的日期范围内（1994-2019）显示质粒携带增加，这可能反映了最近出现的选择压力；它们还与其他类型的ARGs和毒力基因共同发生的情况较少。总的来说，这表明在获得后，质粒ARG倾向于在抗生素选择压力下积累，并与其他适应性基因（其他ARG类型、毒力基因）共同结合，可能通过共同选择重新加强质粒ARG的携带。
Abstract
Plasmids are major vectors of bacterial antibiotic resistance, but understanding of factors associated with plasmid antibiotic resistance gene (ARG) carriage is limited. We curated > 14,000 publicly available plasmid genomes and associated metadata. Duplicate and replicate plasmids were excluded; where possible, sample metadata was validated externally (BacDive database). Using Generalised Additive Models (GAMs) we assessed the influence of 12 biotic/abiotic factors (e.g. plasmid genetic factors, isolation source, collection date) on ARG carriage, modelled as a binary outcome. Separate GAMs were built for 10 major ARG types. Multivariable analysis indicated that plasmid ARG carriage patterns across time (collection years), isolation sources (human/livestock) and host bacterial taxa were consistent with antibiotic selection pressure as a driver of plasmid-mediated antibiotic resistance. Only 0.42% livestock plasmids carried carbapenem resistance (compared with 12% human plasmids); conversely, tetracycline resistance was enriched in livestock vs human plasmids, reflecting known prescribing practices. Interpreting results using a timeline of ARG type acquisition (determined by literature review) yielded additional novel insights. More recently acquired ARG types (e.g. colistin and carbapenem) showed increases in plasmid carriage during the date range analysed (1994–2019), potentially reflecting recent onset of selection pressure; they also co-occurred less commonly with ARGs of other types, and virulence genes. Overall, this suggests that following acquisition, plasmid ARGs tend to accumulate under antibiotic selection pressure and co-associate with other adaptive genes (other ARG types, virulence genes), potentially re-enforcing plasmid ARG carriage through co-selection.

https://www.nature.com/articles/s41598-023-29530-y