Date Published: February 10, 2009
Publisher: Public Library of Science
Author(s): Andreas Sandgren, Michael Strong, Preetika Muthukrishnan, Brian K Weiner, George M Church, Megan B Murray
Abstract: Andreas Sandgren and colleagues describe a new comprehensive resource on drug resistance mutations inM. tuberculosis.
Partial Text: Tuberculosis (TB) remains the leading cause of death from a largely preventable and curable infectious disease, with an estimated 1.7 million deaths in 2006 . Global prospects for TB control are challenged by the emergence of drug-resistant strains, especially those that are multidrug resistant (MDR) and extensively drug resistant (XDR) .
Drug resistance in TB is believed to be mediated exclusively by chromosomal mutations, which affect either the drug target itself or bacterial enzymes that activate prodrugs. Since the early 1990s, numerous studies have described the genetic mechanisms of drug resistance in Mycobacterium tuberculosis, and a wealth of data has accumulated on the mutations found in isolates resistant to specific drugs . For some drugs, like isoniazid and rifampicin, a large number of mutations have been identified that confer resistance, and these mutations account for most of the resistance found among clinical isolates. For other drugs, such as streptomycin and many of the second-line drugs, known drug resistance mutations occur in only a small proportion of resistant isolates . As resistance has become even more prevalent, and high-throughput sequencing methods and genotyping strategies have been developed and refined, large-scale studies to identify the mutations associated with resistance have been undertaken throughout the world. Until now, there has been no single resource where such drug resistance mutation data are readily available to use in research and development. In order to propel the use of the data that are scattered over a large number of publications, many of which are not readily accessible to researchers around the globe, we have compiled the data available on drug resistance mutations in M. tuberculosis in an open-access database that can be used for a diverse array of purposes.
Centralized databases, curated from the literature or high-throughput experiments [6,7], have helped usher in the era of systems biology , and have helped researchers identify global trends and important biological features that would have only been apparent through a comprehensive analysis of the combined data . Examples include protein–protein interaction databases [10,11], genomic databases [12,13], and microarray databases [14–16]. Through this project we present a new database devoted to drug resistance mutations in TB, called the TB Drug Resistance Mutation Database (TBDReaMDB). By providing a comprehensive, single resource of drug resistance mutations in TB, we hope to accelerate and encourage new discoveries that will have applications ranging from diagnostics to drug discovery. We envision that this database will expand as additional mutations are identified in the coming years and will serve as a platform for diverse analyses and projects. TBDReaMDB also complements other TB-related databases such as TBDB (http://www.tbdb.org/), a recently developed Web-based resource housing both annotated genome sequence data and expression data from M. tuberculosis and related species .
TBDReaMDB is a comprehensive resource on drug resistance mutations in M. tuberculosis. We conducted a systematic review (see Text S1 for a brief description of the systematic review strategy) to identify drug resistance mutations from the existing literature to include in the database. We chose not to make any a priori decisions as to whether the mutations described in the literature actually confer drug resistance or are possible secondary compensatory mutations, but instead included all mutations that have been described in drug-resistant strains more often than drug-sensitive isolates. For each mutation, the database provides complete codon changes for each mutation at both the nucleotide and amino acid level.
We have created an interactive Web site that allows users to visualize all the specific mutations associated with resistance to each drug (http://www.tbdreamdb.com/). For more information on the TBDReaMDB Web site, please see Box 1. We envision that this Web site, in addition to presenting the literature in a manually curated database, also will serve as a gateway to post data from future research and development undertaken by its users. In keeping with the scientific philosophy of open access to the public, the database is open to the public and free under the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/). We hope that the Web site will be a portal to communicate future research on drug resistance mechanisms, and to spur development of novel rapid diagnostic tools and drug discovery.
The current version of TBDReaMDB, as of September 1, 2008, is based on literature available up to January 2008. The database will be kept updated and manually curated to provide an accurate picture of the current distribution of mutations associated with drug resistance in TB. To maintain the database up to date, we will include new information submitted to the mutations lists and mutation prevalence data sets.
This project is meant to equip the efforts on research and development of novel technologies and approaches needed for the global surveillance and control of drug-resistant M. tuberculosis, as well as for the diagnosis and clinical care of individual patients with this disease. We have assembled a comprehensive database of putative and well-established resistance mutations and presented the relative frequency and geographical distribution of the most common high-confidence mutations. TBDReaMDB is currently the largest and only open-access database for mutations associated with drug-resistant TB. The most important aspect of this project is that all the data are readily available for open access through a publicly accessible Web site. These data constitute an important resource for the TB research community and others to spur further research on drug resistance mechanisms that eventually may lead to the development of novel diagnostic tools and therapeutics to combat resistant TB.