Article Figures & Data
Figures
- Fig 1
Presentation of the Staphylococcus aureus blaZ ß-lactamase gene in the CARD. (A) The gene's Web page in the CARD, providing annotation, accession, source information, ontological classification (SO, ARO, GO), and associated molecular features (mRNA, polypeptide, coding sequence [CDS]). (B) Dynamic browsing and analysis of the blaZ gene using the Web-based genome visualization and analysis tool GBrowse.
- Fig 2
Classification of aminocoumarin-resistant gyrase B in the Antibiotic Resistance Ontology (ARO), illustrating the use of ontological relationships to describe knowledge about the gene (see Table 3). The is_a relationships are depicted by solid arrows labeled with “i” and generally denote classification hierarchies within the major branches of the ARO (mechanism, determinant, antibiotic, target), while dashed arrows labeled with “p” reflect part_of relationships between genes and mechanisms. Dashed arrows labeled with “d” depict derived_from relationships between antibiotic-sensitive precursors and antibiotic-resistant forms of the gene, while those labeled with “t” reflect targeted_by relationships between antibiotic-sensitive forms and antibiotic molecules. Dashed arrows labeled with “r” depict confers_resistance relationships between antibiotic resistance genes and antibiotic molecules. Asterisks denote a derived_from relationship between antibiotic-resistant and -sensitive DNA topoisomerase subunits.
- Fig 3
Organization of aminoglycoside antibiotics (blue), their target (green), and aminoglycoside resistance genes (red) in the CARD's Antibiotic Resistance Ontology, illustrating the diversity of genes providing resistance to single or multiple aminoglycosides. Nodes represent ontology terms, while edges represent relationships between ontology terms.
- Fig 4
An ontology term Web page for tetracycline resistance gene tetX (ARO:3000205) in the CARD, providing descriptive, ontological classification, sequence, protein structure, publication, taxonomic distribution, and bioinformatics data/model information. By providing an ontology-centered interface, the CARD offers a clearinghouse of information on antibiotic resistance genes, mechanisms, drugs, etc. The left column reflects ontological cross-referencing (see Materials and Methods).
- Fig 5
Analysis of the whole genome of Acinetobacter baumannii strain TCDC-AB0715 by the Resistance Gene Identifier (RGI). The A. baumannii strain TCDC-AB0715 is a clinical isolate with resistance to carbapenems, fluoroquinolones, and cephalosporins (26). (A) “Resistance wheel” for A. baumannii strain TCDC-AB0715, predicting resistance to a broad range of antibiotic classes. (B) Details screen of orf0_267, illustrating detection of the aminoglycoside nucleotidyltransferase ANT(3″). (C) Open reading frame (ORF) map of a region of the A. baumannii strain TCDC-AB0715 chromosome, with prediction of β-lactamases TEM-1 and TEM-33 (light blue), aminoglycoside phosphotransferases, nucleotidyltransferases, and acetyltransferases (pink), chloramphenicol acetyltransferase (bright green), sulfonamide-resistant dihydropteroate synthase sul1 (dark green), tetracycline efflux pump tetB (dark pink), and genes implicated in general efflux (dark blue). ORFs unrelated to antibiotic resistance are presented in gray, while non-protein-coding regions are presented in black. The resistance genes identified are consistent with the reported resistance phenotype (26).
Tables
- Table 1
List of antibiotic resistance genes curated in the CARD within which citation, molecular sequence, protein structure, mechanism, and ARO classification details are provideda
Aminocoumarins Aminocoumarin-resistant DNA topoisomerases Aminocoumarin-resistant GyrB, ParE, ParY Aminoglycosides Aminoglycoside acetyltransferases AAC(1), AAC(2′), AAC(3), AAC(6′) Aminoglycoside nucleotidyltransferases ANT(2″), ANT(3″), ANT(4′), ANT(6), ANT(9) Aminoglycoside phosphotransferases APH(2″), APH(3″), APH(3′), APH(4), APH(6), APH(7″), APH(9) 16S rRNA methyltransferases ArmA, RmtA, RmtB, RmtC, Sgm β-Lactams Class A β-lactamases AER, BLA1, CTX-M, KPC, SHV, TEM, etc.b Class B (metallo-)β-lactamases BlaB, CcrA, IMP, NDM, VIM, etc.b Class C β-lactamases ACT, AmpC, CMY, LAT, PDC, etc.b Class D β-lactamases OXA β-lactamaseb mecA (methicillin-resistant PBP2) Mutant porin proteins conferring antibiotic resistance Antibiotic-resistant Omp36, OmpF, PIB (por) Genes modulating β-lactam resistance bla (blaI, blaR1) and mec (mecI, mecR1) operons Chloramphenicol Chloramphenicol acetyltransferase (CAT) Chloramphenicol phosphotransferase Ethambutol Ethambutol-resistant arabinosyltransferase (EmbB) Mupirocin Mupirocin-resistant isoleucyl-tRNA synthetases MupA, MupB Peptide antibiotics Integral membrane protein MprF Phenicol Cfr 23S rRNA methyltransferase Rifampin Rifampin ADP-ribosyltransferase (Arr) Rifampin glycosyltransferase Rifampin monooxygenase Rifampin phosphotransferase Rifampin resistance RNA polymerase-binding proteins DnaA, RbpA Rifampin-resistant beta-subunit of RNA polymerase (RpoB) Streptogramins Cfr 23S rRNA methyltransferase Erm 23S rRNA methyltransferases ErmA, ErmB, Erm(31), etc.d Streptogramin resistance ATP-binding cassette (ABC) efflux pumps Lsa, MsrA, Vga, VgaB Streptogramin Vgb lyase Vat acetyltransferase Fluoroquinolones Fluoroquinolone acetyltransferase Fluoroquinolone-resistant DNA topoisomerases Fluoroquinolone-resistant GyrA, GyrB, ParC Quinolone resistance protein (Qnr) Fosfomycin Fosfomycin phosphotransferases FomA, FomB, FosC Fosfomycin thiol transferases FosA, FosB, FosX Glycopeptides VanA, VanB, VanD, VanR, VanS, etc.c Lincosamides Cfr 23S rRNA methyltransferase Erm 23S rRNA methyltransferases ErmA, ErmB, Erm(31), etc.d Lincosamide nucleotidyltransferase (Lin) Linezolid Cfr 23S rRNA methyltransferase Macrolides Cfr 23S rRNA methyltransferase Erm 23S rRNA methyltransferases ErmA, ErmB, Erm(31), etc.d Macrolide esterases EreA, EreB Macrolide glycosyltransferases GimA, Mgt, Ole Macrolide phosphotransferases (MPH) MPH(2′)-I, MPH(2′)-II Macrolide resistance efflux pumps MefA, MefE, Mel Streptothricin Streptothricin acetyltransferase (sat) Sulfonamides Sulfonamide-resistant dihydropteroate synthases Sul1, Sul2, Sul3, sulfonamide-resistant FolP Tetracyclines Mutant porin PIB (por) with reduced permeability Tetracycline inactivation enzyme TetX Tetracycline resistance major facilitator superfamily (MFS) efflux pumps TetA, TetB, TetC, Tet30, Tet31, etc.e Tetracycline resistance ribosomal protection proteins TetM, TetO, TetQ, Tet32, Tet36, etc.e Efflux pumps conferring antibiotic resistance ABC antibiotic efflux pump MacAB-TolC, MsbA, MsrA,VgaB, etc.f MFS antibiotic efflux pump EmrD, EmrAB-TolC, NorB, GepA, etc.f Multidrug and toxic compound extrusion (MATE) transporter MepA Resistance-nodulation-cell division (RND) efflux pump AdeABC, AcrD, MexAB-OprM, mtrCDE, etc.f Small multidrug resistance (SMR) antibiotic efflux pump EmrE Genes modulating antibiotic efflux adeR, acrR, baeSR, mexR, phoPQ, mtrR, etc.g ↵a ARO, Antibiotic Resistance Ontology.
↵b Complete lists of β-lactamase families and individual β-lactamases can be found in the CARD.
↵c Glycopeptide resistance gene clusters include a number of genes encoding proteins with different functions, including sensors, regulators, and enzymes, all of which result in restructuring of the cell wall, providing resistance to glycopeptides. The full list of genes involved can be found in the CARD.
↵d Complete lists of Erm 23S rRNA methyltransferases can be found in the CARD.
↵e Complete lists of tetracycline resistance major facilitator superfamily (MFS) efflux pumps and ribosomal protection proteins can be found in the CARD.
↵f Complete lists of ATP-binding cassette (ABC), MFS, and resistance-nodulation-cell division (RND) antibiotic efflux pumps can be found in the CARD.
↵g Complete lists of efflux regulatory proteins can be found in the CARD, including information on mutations conferring increased rates of antibiotic efflux.
- Table 2
Major branches of the AROa
Major ARO branch Scope Determinant of Antibiotic Resistance (ARO:3000000) Antibiotic resistance genes, SNPs, or other molecular entities organized by target (e.g., aminocoumarin, glycopeptides, etc.) and mode of action (e.g., antibiotic inactivation, molecular bypass, etc.) Mechanism of Antibiotic Resistance (ARO:1000002) Target alteration, target replacement, antibiotic inactivation, antibiotic efflux, antibiotic target protection, reduced permeability to antibiotic Antibiotic Target (ARO:3000708) Targeted cell membrane components, protein or nucleotide synthesis machinery, enzymes, etc. Antibiotic Molecule (ARO:1000003) Hierarchical classification of antibiotics (e.g., sulfonamide, β-lactam, glycopeptide antibiotics, etc.) Inhibitor of Antibiotic Resistance (ARO:0000076) β-Lactamase and other inhibitors Antibiotic Biosynthesis (ARO:3000082) Phosphonoacetaldehyde methyltransfererase, glycopeptide biosynthesis, macrolide biosynthesis, streptogramin biosynthesis, fosfomycin biosynthesis, aminocoumarin biosynthesis, phosphoenolpyruvate (PEP) mutase, phosphonopyruvate decarboxylase Antibiotic Resistance Terminology (ARO:3000045) Ontological relationship types, bioinformatic model types, reference molecular sequence types, etc. ↵a ARO, Antibiotic Resistance Ontology. All major branches are part_of ARO:1000001, “process or component of antibiotic biology or chemistry.”
- Table 3
Relationship types used within the AROa
Relationship type Description Source is_a An axiomatic relationship ontology term in which the subject is placed into a higher order classification RO part_of A relationship ontology term in which the subject is but part of the object RO derives_from A relationship ontology term in which the subject has its origins in the object RO regulates A relationship ontology term in which the subject regulates expression of the object ARO confers_resistance_to A relationship ontology term in which the subject confers antibiotic resistance to the object ARO confers_resistance_to_drug A relationship ontology term in which the subject (usually a gene) confers clinically relevant resistance to a specific antibiotic ARO targeted_by A relationship ontology term in which the subject is targeted by the object (usually a class of antibiotics) ARO targeted_by_drug A relationship ontology term in which the subject is targeted by a specific antibiotic ARO ↵a ARO, Antibiotic Resistance Ontology; RO, Relation Ontology, a part of the Open Biological and Biomedical Ontologies resource (27). Descriptions are paraphrased.
