The Comprehensive Antibiotic Resistance Database A Platform for Antimicrobial Resistance Surveillance Andrew G. McArthur, Ph.D. Michael G. DeGroote Institute for Infectious Disease Research McMaster University, Hamilton, Ontario, Canada arpcard.mcmaster.ca
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The Comprehensive Antibiotic Resistance Database A Platform for Antimicrobial Resistance Surveillance
Andrew G. McArthur, Ph.D.
Michael G. DeGroote Institute for Infectious Disease Research
McMaster University, Hamilton, Ontario, Canada
arpcard.mcmaster.ca
Global AMR Crisis
Which resistance genes are present?
Which genes are moving around?
Which pose a threat?
NDM-1 metallo-beta-lactamase
Promise of Molecular Surveillance
Promise of Molecular Surveillance
retrospective & survey
DNA sequencing
clinical DNA
sequencing
Promise of Molecular Surveillance
PHAC’s ‘One Health’ Concept
Wright. 2010. Expert Opin. Drug Discov. 5:779-788.
A Wicked Problem
• No single solution – but critical demand for action
• Very complex – requires the combined expertise of many individuals,
groups, and disciplines
• Working in ‘silos’ without collaboration does not solve wicked problems
• Solutions require a very comprehensive and interdisciplinary strategy
• AMR gene surveillance a key component
A Wicked Problem
A Wicked Problem
genes and
pathogens we are
tracking
A Wicked Problem
genes and
pathogens we are
tracking
characterized genes
we don’t routinely
track; variants of
known genes
A Wicked Problem
genes and
pathogens we are
tracking
characterized genes
we don’t routinely
track; variants of
known genes
emergent threats
Promise of Molecular Surveillance
DNA sequencing
prediction of
phenotype &
antibiogram
comparison to reference
sequences
prediction of
resistome
Comprehensive Antibiotic Resistance Database
arpcard.mcmaster.ca
Comprehensive Antibiotic Resistance Database
• High quality reference data on the molecular basis of AMR – expert
curation.
• Organized by the Antibiotic Resistance Ontology (ARO), a theoretical
framework for organizing antibiotic resistance information.
• Breadth of data – AMR via horizontal gene transfer (HGT) +
comprehensive mutation data for genome-based AMR.
• Advanced analytics – predicts resistome based on both sequence
similarity and mutant detection.
• Discovery – development of methods for detection of new variants and
emergent threats
• Growth – constantly curated resource + building algorithms for
detection of AMR mechanisms not examined by other databases (rRNA
mutations, van clusters, etc.)
Comprehensive Antibiotic Resistance Database
• A controlled vocabulary for the codification of drugs, targets, resistance
genes, and mechanisms.
• Resistance terms are linked together by a set of relationships.
• Allows for computation over a network of curated AMR knowledge.
• An essential step towards the development of standards for data sharing
among research teams.
• Development to date has been a scrum-style accumulation of ontology
terms and metadata
• Now moving to systematic approaches to ARO development
• ESKAPE pathogens
• Formal ontology structures
• Computer-assisted literature curation
Antibiotic Resistance Ontology
Antibiotic Resistance Ontology
Detection Model Ontology
DNA sequencing
prediction of
phenotype &
antibiogram
comparison to reference
sequences
prediction of
resistome
detection models &
parameters
Detection Model Ontology
• protein homolog model
• protein variant model
• rRNA mutation model
• absent protein homolog model – resistance by absence
• gene order model – functional glycopeptide resistance clusters
• multiple gene mutations model – resistance by co-mutation
• regulatory models – efflux upregulation by mutations in promoters
Detection Model Ontology
• protein homolog model
• reference sequence
• BLASTP cut-off
Detection Model Ontology
• protein variant model
• reference sequence (often sensitive wildtype)
• BLASTP cut-off
• Mutations – SNPs, indels, etc.
Detection Model Ontology
• gene order meta-model
• secondary interpretation of resistome predictions