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- Title
Structural and molecular rationale for the diversification of resistance mediated by the Antibiotic_NAT family.
- Authors
Stogios, Peter J.; Bordeleau, Emily; Xu, Zhiyu; Skarina, Tatiana; Evdokimova, Elena; Chou, Sommer; Diorio-Toth, Luke; D'Souza, Alaric W.; Patel, Sanket; Dantas, Gautam; Wright, Gerard D.; Savchenko, Alexei
- 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. A comprehensive functional and structural study of the Antibiotic_NAT family of aminoglycoside acetyltransferases provides new insight into the molecular mechanisms underlying resistance to existing and emerging aminoglycoside antibiotics.
- Subjects
DRUG resistance in bacteria; FUNCTIONAL analysis; PATHOGENIC bacteria; ACETYLTRANSFERASES; ANTIBIOTICS; ENVIRONMENTAL sampling
- Publication
Communications Biology, 2022, Vol 5, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-022-03219-w