Comprehensive Antibiotic Resistance Database

Last updated
The Comprehensive Antibiotic Resistance Database
McArthur Lab Logo.png
Content
DescriptionThe Comprehensive Antibiotic Resistance Database provides data, models, and algorithms relating to the molecular basis of antimicrobial resistance.
Data types
captured		Antimicrobial resistance genes and phenotypes
Organisms Bacteria
Contact
Research center McMaster University
Primary citation PMID   27789705
Access
Website card.mcmaster.ca
Download URL Download
Miscellaneous
Bookmarkable
entities		yes

The Comprehensive Antibiotic Resistance Database (CARD) is a biological database that collects and organizes reference information on antimicrobial resistance genes, proteins and phenotypes. [1] [2] The database covers all types of drug classes and resistance mechanisms and structures its data based on an ontology. The CARD database was one of the first resources that covered antimicrobial resistance genes. [3] The resource is updated monthly [4] and provides tools to allow users to find potential antibiotic resistance genes in newly-sequenced genomes.

Contents

Ontology

Each resistance determinant described by the CARD Antibiotic Resistance Ontology (ARO) must include a connection to each of three branches: Determinant of Antibiotic Resistance, Antibiotic Molecule and Mechanism of Antibiotic Resistance. CARD has recently also launched draft ontologies for both virulence and mobile genetic elements, which are in active development. [1]

Curation

CARD curation occurs continuously, with monthly updates released by a team of biocurators. The curation process primarily involves regular review of the available scientific literature. Enforced curation guidelines provide the necessary context to ensure proper hierarchical classification, defined semantic relationships and data standardization. The biocuration team additionally annotates each ARO term with supplemental information from external references, including relevant publications, chemical structures or protein structure via the Protein Data Bank. ARO terms for AMR determinants are paired with an AMR detection model, which includes the nucleotide and peptide sequence retrieved from NCBI GenBank and any additional parameters needed for prediction of the determinant from raw DNA sequence. Curation is sometimes supplemented with de novo analyses, often to resolve problematic nomenclature. [1]

Overall, CARD’s primary curation paradigm is as follows: to be included in CARD an AMR determinant must be described in a peer-reviewed scientific publication, with its DNA sequence available in GenBank, including clear experimental evidence of elevated minimum inhibitory concentration (MIC) over controls. AMR genes predicted by in silico methods, but not experimentally characterized, are not included in CARD’s primary curation. Yet, data harmonization efforts in 2019 that involved a comparison of ResFinder, ARG-ANNOT and NCBI’s catalog of β-lactamase alleles, revealed a large number of historical β-lactamases without associated peer-reviewed publication. As β-lactamases comprise nearly a third of ARO terms in CARD, that convention leads to each β-lactamase sequence variant being given a new name in the literature and missing β-lactamase reference sequences in CARD, leading to annotation imprecision by RGI and notable content differences between CARD and other databases. CARD now includes β-lactamase reference sequences and names even if they lack published experimental evidence of elevated MIC. This back-curation of older β-lactamase sequences is ongoing. [1]

While a large part of CARD’s value is expert human biocuration of AMR sequence data and its relationship to antibiotics, with AMR publications in PubMed exceeding over 5000 per year for the last 10 years the task of keeping CARD both comprehensive and up-to-date is daunting. CARD addresses this problem using three approaches: ad hoc biocuration, pathogen AMR reviews, and computer-assisted literature triage. Ad hoc biocuration involves addressing feedback from the AMR research community as well as literature discovered during quality-control checks or review of AMR gene nomenclature. Pathogen AMR review involves systematic review of the AMR literature for specific pathogens. In 2017, the CARD*Shark text-mining algorithm was introduced for computer-assisted literature triage, which has been expanded based on the new ARO Drug Class classification tags. CARD*Shark assigns priority scores to publications from a general PubMed Medical Subject Headings (MeSH) search based on relevance and assigns the results to a CARD biocurator for manual review. [1]

The CARD curation team continuously updates the database on a development server and prior to release, rigorous QC scripts are implemented to validate these data before porting it to the publicly available website. These QC steps verify the use of external identifiers, publication citations, AMR detection model parameters and imposed rules for the ontology structure. Any detected issues are resolved prior to release. After QC, the public CARD website is updated monthly. The website also includes a built-in BLAST instance for comparing sequences to CARD reference sequences and a web instance of RGI for resistome prediction with data visualization tools. [1]

Community involvement

In response to the 2019 European Commission's Joint Research Centre (JRC) AMR Databases Workshop, the ‘AMR_Curation’ public repository was established for collective curation of AMR genes and mutations involving the majority of AMR database curators (e.g. NCBI, Resfinder, MEGARes, etc.) with an active and monitored curation issue tracker, a parallel AMR curation mailing list, editable Google Spreadsheet List of AMR Databases and Software, and curated Wikipedia list of AMR Databases all accessible at https://github.com/arpcard/amr_curation. CAD encourages researchers, software developers and AMR data curators to use this repository and associated resources to submit, discuss and resolve AMR curation issues. Anyone with a GitHub account can submit an issue. [1]

AMR detection models

CARD’s Model Ontology includes reference nucleotide and protein sequences, as well as additional search parameters including mutations conferring AMR (if applicable) and curated BLAST(P/N) bit score cut-offs. The majority of CARD AMR determinants use either a protein homolog model (PHM) or a protein variant model (PVM). PHMs predict AMR protein sequences from raw DNA sequence based on homology to a curated reference sequence, based on a curated BLAST bit score cut-off. PVMs perform a similar search, but include additional parameters for the detection of specific curated non-synonymous mutations or other genetic variants (i.e. INDELs, frameshifts) that differentiate between antibiotic-susceptible wild-type and antibiotic-resistant alleles. [1]

From 2017, CARD transitioned each detection model to curated BLAST bit score cut-offs, discontinuing use of less discriminatory BLAST expectation values (E). Bit score cut-offs are selected based on values that perform this discrimination when the curated reference sequence is compared by BLAST against CARD itself and against GenBank's non-redundant database, with hand inspection to determine a value that correctly classifies matches as homologs of similar antimicrobial function or similar proteins with different function or AMR Gene Family membership. The asymptotic nature of the BLAST expectation value (E) gave it very low discriminatory power between different β-lactamase gene families (nearly ⅓ of CARD’s content), but the linear nature of the BLAST bit score allowed this level of discrimination. [1]

See also

Related Research Articles

<span class="mw-page-title-main">Antimicrobial resistance</span> Resistance of microbes to drugs directed against them

Antimicrobial resistance (AMR) occurs when microbes evolve mechanisms that protect them from the effects of antimicrobials. All classes of microbes can evolve resistance where the drugs are no longer effective. Fungi evolve antifungal resistance. Viruses evolve antiviral resistance. Protozoa evolve antiprotozoal resistance, and bacteria evolve antibiotic resistance. Together all of these come under the umbrella of antimicrobial resistance. Microbes resistant to multiple antimicrobials are called multidrug resistant (MDR) and are sometimes referred to as superbugs. Although antimicrobial resistance is a naturally occurring process, it is often the result of improper usage of the drugs and management of the infections.

<span class="mw-page-title-main">Beta-lactamase</span> Class of enzymes

Beta-lactamases (β-lactamases) are enzymes produced by bacteria that provide multi-resistance to beta-lactam antibiotics such as penicillins, cephalosporins, cephamycins, monobactams and carbapenems (ertapenem), although carbapenems are relatively resistant to beta-lactamase. Beta-lactamase provides antibiotic resistance by breaking the antibiotics' structure. These antibiotics all have a common element in their molecular structure: a four-atom ring known as a beta-lactam (β-lactam) ring. Through hydrolysis, the enzyme lactamase breaks the β-lactam ring open, deactivating the molecule's antibacterial properties.

<span class="mw-page-title-main">Methicillin</span> Antibiotic medication

Methicillin (USAN), also known as meticillin (INN), is a narrow-spectrum β-lactam antibiotic of the penicillin class.

<span class="mw-page-title-main">Clavulanic acid</span> Molecule used to overcome antibiotic resistance in bacteria

Clavulanic acid is a β-lactam drug that functions as a mechanism-based β-lactamase inhibitor. While not effective by itself as an antibiotic, when combined with penicillin-group antibiotics, it can overcome antibiotic resistance in bacteria that secrete β-lactamase, which otherwise inactivates most penicillins.

The Saccharomyces Genome Database (SGD) is a scientific database of the molecular biology and genetics of the yeast Saccharomyces cerevisiae, which is commonly known as baker's or budding yeast. Further information is located at the Yeastract curated repository.

The resistome has been used to describe to two similar yet separate concepts:

Capnocytophaga is a genus of Gram-negative bacteria. Normally found in the oropharyngeal tract of mammals, they are involved in the pathogenesis of some animal bite wounds and periodontal diseases.

β-Lactamase inhibitor Family of enzymes

Beta-lactamases are a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. In bacterial resistance to beta-lactam antibiotics, the bacteria have beta-lactamase which degrade the beta-lactam rings, rendering the antibiotic ineffective. However, with beta-lactamase inhibitors, these enzymes on the bacteria are inhibited, thus allowing the antibiotic to take effect. Strategies for combating this form of resistance have included the development of new beta-lactam antibiotics that are more resistant to cleavage and the development of the class of enzyme inhibitors called beta-lactamase inhibitors. Although β-lactamase inhibitors have little antibiotic activity of their own, they prevent bacterial degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs are effective against.

<span class="mw-page-title-main">Plasmid-mediated resistance</span> Antibiotic resistance caused by a plasmid

Plasmid-mediated resistance is the transfer of antibiotic resistance genes which are carried on plasmids. Plasmids possess mechanisms that ensure their independent replication as well as those that regulate their replication number and guarantee stable inheritance during cell division. By the conjugation process, they can stimulate lateral transfer between bacteria from various genera and kingdoms. Numerous plasmids contain addiction-inducing systems that are typically based on toxin-antitoxin factors and capable of killing daughter cells that don't inherit the plasmid during cell division. Plasmids often carry multiple antibiotic resistance genes, contributing to the spread of multidrug-resistance (MDR). Antibiotic resistance mediated by MDR plasmids severely limits the treatment options for the infections caused by Gram-negative bacteria, especially family Enterobacteriaceae. The global spread of MDR plasmids has been enhanced by selective pressure from antimicrobial medications used in medical facilities and when raising animals for food.

Cephalosporins are a broad class of bactericidal antibiotics that include the β-lactam ring and share a structural similarity and mechanism of action with other β-lactam antibiotics. The cephalosporins have the ability to kill bacteria by inhibiting essential steps in the bacterial cell wall synthesis which in the end results in osmotic lysis and death of the bacterial cell. Cephalosporins are widely used antibiotics because of their clinical efficiency and desirable safety profile.

MEGARes is a hand-curated antibiotic resistance database which incorporates previously published resistance sequences for antimicrobial drugs, while also expanding to include published sequences for metal and biocide resistance determinants. In MEGARes 3.0, the nodes of the acyclic hierarchical ontology include four antimicrobial compound types, 59 classes, 223 mechanisms of resistance, and 1,448 gene groups that classify the 8,733 gene accessions. This works in conjunction with the AMR++ bioinformatics pipelin to classify resistome sequences directly from FASTA.

Mustard is a database that tracks Antimicrobial Resistance Determinants (ARDs). The method by which it tracks ARDs is using their own method adapted from Protein Homology Modelling called Pairwise Comparative Modelling (PCM), which increase specificity protein prediction, especially for distantly related protein homologues. Using PCM, 6095 ARDs from 20 families in the human gut microbiota. Antibiotic resistance databases used were ResFinder, ARG-ANNOT, the now defunct Lahey Clinic, Marilyn Roberts website for tetracycline and macrolide resistance genes and metagenomics.

FARME also known as Functional Antibiotic Resistance Metagenomic Element is a database that compiles publicly available DNA elements and predicted proteins that confer antibiotic resistance, regulatory elements and mobile genetic elements. It is the first database to focus on functional metagenomics. This allows the database to understand 99% of bacteria which cannot be cultured, the relationship between environmental antibiotic resistance sequences and antibiotic genes derived from cultured isolates. This information was derived from 20 metagenomics projects from GenBank. Also from GenBank are the protein sequence predictions and annotations.

The Beta-Lactamase Database (BLAD) is a web-based antimicrobial resistance database that provides structural and phenotypic data on a class of enzymes, beta-lactamase. It hosts sequences from all classes of metallo and non-metallo beta-lactamases. The resource has approximately 2000 gene sequences and compiles its data from various literature, NCBI, protein data bank and other mediums. BLAD is based at the Aligarh Muslim University in the Interdisciplinary Biotechnology Unit. BLAD has four search fields on their site: database, resistance, PDBS, and genome.

CBMAR otherwise known as Comprehensive β-lactamase Molecular Annotation Resource is a database focused on the annotation and discovery of novel beta-lactamase genes and proteins in bacteria. Beta-lactamases are characterized on CBMAR using the Ambler Classification system. CBMAR organizes beta-lactamases according to their classes: A, B, C, and D. They are then further categorized by their (i) sequence variability, (ii) antibiotic resistance profile, (iii) inhibitor susceptibility, (iv) active site, (v) family fingerprints, (vi) mutational profile, (vii) variants, (viii) gene location, (ix) phylogenetic tree, etc. The primary sources of database for CBMAR are GenBank and Uniprot. CBMAR is built on an Apache HTTP Server 2.2.17 with MySQL Ver 14.14 and hosted on Ubuntu 11.04 Linux platform.

RAC otherwise known as Repository of Antibiotic resistance Cassettes is a database that uses the automatic Attacca annotation system in order to comprehensively annotate gene-cassettes and transposable elements in a stream-lined manner and to discover novel gene cassettes. Antibiotic resistance is often due to horizontal gene transfer, which allows resistance to arise through cell-to-cell interaction. This poses a major challenge in the field of antibiotic resistance. Hence, the creation of RAC which would provide researchers a comprehensive and unique tool for the endeavor of documenting resistance due to gene-cassettes and transposable elements. Attacca helps discover novel gene cassettes when any three of the following occurs as mentioned in Tsafnat et al, 2011:

The SARG database also known as Structured Antibiotic Resistance Gene database is a collection of antimicrobial resistance genes. The hierarchical structure of the database is clear to be 1) Type: antibiotic type 2) Subtype: genotype 3) Sequence: reference sequence. The SARG database helps in quick survey of antimicrobial resistance genes from environmental samples. The database was initially integrated from ARDB and Comprehensive Antibiotic Resistance Database, followed by hand curation including removing non-ARG sequences, removing redundant sequences and SNP sequences. Other sources include NCBI nr database and published papers.

Biocuration is the field of life sciences dedicated to organizing biomedical data, information and knowledge into structured formats, such as spreadsheets, tables and knowledge graphs. The biocuration of biomedical knowledge is made possible by the cooperative work of biocurators, software developers and bioinformaticians and is at the base of the work of biological databases.

The AMRFinderPlus tool from the National Center for Biotechnology Information (NCBI) is a bioinformatic tool that allows users to identify antimicrobial resistance determinants, stress response, and virulence genes in bacterial genomes. This tool's development began in 2018 and is still underway. The National Institutes of Health funds the development of the software and the databases it uses.

References

  1. 1 2 3 4 5 6 7 8 9 Alcock BP, Raphenya AR, Lau TTY, Tsang KK, Bouchard M, Edalatmand A; et al. (2020). "CARD 2020: antibiotic resistome surveillance with the comprehensive antibiotic resistance database". Nucleic Acids Res. 48 (D1): D517–D525. doi:10.1093/nar/gkz935. PMC   7145624 . PMID   31665441.{{cite journal}}: CS1 maint: multiple names: authors list (link) Creative Commons by small.svg  This article incorporates text available under the CC BY 4.0 license.
  2. ↑ Jia, B; Raphenya, AR; Alcock, B; Waglechner, N; Guo, P; Tsang, KK; Lago, BA; Dave, BM; Pereira, S; Sharma, AN; Doshi, S; Courtot, M; Lo, R; Williams, LE; Frye, JG; Elsayegh, T; Sardar, D; Westman, EL; Pawlowski, AC; Johnson, TA; Brinkman, FS; Wright, GD; McArthur, AG (4 January 2017). "CARD 2017: expansion and model-centric curation of the comprehensive antibiotic resistance database". Nucleic Acids Research. 45 (D1): D566–D573. doi:10.1093/nar/gkw1004. PMC   5210516 . PMID   27789705.
  3. ↑ McArthur, AG; Waglechner, N; Nizam, F; Yan, A; Azad, MA; Baylay, AJ; Bhullar, K; Canova, MJ; De Pascale, G; Ejim, L; Kalan, L; King, AM; Koteva, K; Morar, M; Mulvey, MR; O'Brien, JS; Pawlowski, AC; Piddock, LJ; Spanogiannopoulos, P; Sutherland, AD; Tang, I; Taylor, PL; Thaker, M; Wang, W; Yan, M; Yu, T; Wright, GD (July 2013). "The comprehensive antibiotic resistance database". Antimicrobial Agents and Chemotherapy. 57 (7): 3348–57. doi:10.1128/AAC.00419-13. PMC   3697360 . PMID   23650175.
  4. ↑ "CARD website" . Retrieved 5 June 2020.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.