摘要
      环境微生物组包含大量抗生素抗性基因（ARGs），这些基因可以作为病原菌中发现的ARGs的进化前身，也可以在存在选择压力的情况下直接动员到病原体中。因此，来自良性环境细菌的ARGs是了解临床相关耐药性的重要来源。在这里，我们对氨基糖苷乙酰转移酶的抗生素NAT家族进行了全面的功能分析。我们测定了21种抗生素NAT酶的泛家族抗体谱，其中8种来自临床分离株，13种来自环境宏基因组样本。我们发现，环境衍生的代表物具有高水平的广谱耐药性，包括对非典型氨基糖苷类安普霉素的耐药性，并且宏基因组衍生的基因可能是临床分离株中发现的aac（3）基因的祖先。通过晶体学分析，我们合理化了整个家族底物特异性多样化的分子基础。这项工作提供了支持对已建立和新出现的氨基糖苷类抗生素耐药性的分子机制的关键数据，并拓宽了我们对环境中ARGs的理解。
Abstract
The environmental microbiome harbors a vast repertoire of antibiotic resistance genes (ARGs) which can serve as evolutionary predecessors for ARGs found in pathogenic bacteria, or can be directly mobilized to pathogens in the presence of selection pressures. Thus, ARGs from benign environmental bacteria are an important resource for understanding clinically relevant resistance. Here, we conduct a comprehensive functional analysis of the Antibiotic_NAT family of aminoglycoside acetyltransferases. We determined a pan-family antibiogram of 21 Antibiotic_NAT enzymes, including 8 derived from clinical isolates and 13 from environmental metagenomic samples. We find that environment-derived representatives confer high-level, broad-spectrum resistance, including against the atypical aminoglycoside apramycin, and that a metagenome-derived gene likely is ancestral to an aac(3) gene found in clinical isolates. Through crystallographic analysis, we rationalize the molecular basis for diversification of substrate specificity across the family. This work provides critical data on the molecular mechanism underpinning resistance to established and emergent aminoglycoside antibiotics and broadens our understanding of ARGs in the environment.

https://www.nature.com/articles/s42003-022-03219-w