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Title: Structural and Functional Survey of Environmental Aminoglycoside Acetyltransferases Reveals Functionality of Resistance Enzymes

Journal Article · · ACS Infectious Diseases
 [1];  [2];  [1];  [3];  [3];  [2];  [1];  [1];  [4]; ORCiD logo [2]
  1. Univ. of Toronto, ON (Canada)
  2. Univ. of Toronto, ON (Canada); Health Research Innovation Center, Calgary, AB (Canada)
  3. Washington Univ. School of Medicine, St. Louis, MO (United States)
  4. Washington Univ. School of Medicine, St. Louis, MO (United States); Washington Univ., St. Louis, MO (United States)
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Aminoglycoside N-acetyltransferases (AACs) confer resistance against the clinical use of aminoglycoside antibiotics. The origin of AACs can be traced to environmental microbial species representing a vast reservoir for new and emerging resistance enzymes, which are currently undercharacterized. In this work, we performed detailed structural characterization and functional analyses of four metagenomic AAC (meta-AACs) enzymes recently identified in a survey of agricultural and grassland soil microbiomes (Forsberg et al. Nature 2014, 509, 612). These enzymes are new members of the Gcn5-Related-N-Acetyltransferase superfamily and confer resistance to the aminoglycosides gentamicin C, sisomicin, and tobramycin. Moreover, the meta-AAC0020 enzyme demonstrated activity comparable with an AAC(3)-I enzyme that serves as a model AAC enzyme identified in a clinical bacterial isolate. The crystal structure of meta-AAC0020 in complex with sisomicin confirmed an unexpected AAC(6') regiospecificity of this enzyme and revealed a drug binding mechanism distinct from previously characterized AAC(6') enzymes. Together, our data highlights the presence of highly active antibiotic-modifying enzymes in the environmental microbiome and reveals unexpected diversity in substrate specificity. These observations of additional AAC enzymes must be considered in the search for novel aminoglycosides less prone to resistance.

Research Organization:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH); National Institute of General Medical Sciences (NIGMS); National Human Genome Research Institute (NHGRI)
Grant/Contract Number:
HHSN272201200026C; DP2-DK-098089; GM 007067; DGE-1143954
OSTI ID:
1544871
Journal Information:
ACS Infectious Diseases, Vol. 3, Issue 9; ISSN 2373-8227
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 6 works
Citation information provided by
Web of Science

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Cited By (1)

Structure of the full‐length Serratia marcescens acetyltransferase AAC(3)‐Ia in complex with coenzyme A journal January 2020

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Related Subjects

60 APPLIED LIFE SCIENCES
antibiotic resistance
resistome
aminoglycosides
acetyltransferase
environmental
crystal structure