Abstract
Tuberculosis treatment includes broad-spectrum antibiotics such as rifampicin, streptomycin and fluoroquinolones, which are also used against other pathogenic bacteria. We developed Drug Resistance Associated Genes database (DRAGdb), a manually curated repository of mutational data of drug resistance associated genes (DRAGs) across ESKAPE (i.e. Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) pathogens, and other bacteria with a special focus on Mycobacterium tuberculosis (MTB). Analysis of mutations in drug-resistant genes listed in DRAGdb suggested both homoplasy and pleiotropy to be associated with resistance. Homoplasy was observed in six genes namely gidB, gyrA, gyrB, rpoB, rpsL and rrs. For these genes, drug resistance-associated mutations at codon level were conserved in MTB, ESKAPE and many other bacteria. Pleiotropy was exemplified by a single nucleotide mutation that was associated with resistance to amikacin, gentamycin, rifampicin and vancomycin in Staphylococcus aureus. DRAGdb data also revealed that mutations in some genes such as pncA, inhA, katG and embA,B,C were specific to Mycobacterium species. For inhA and pncA, the mutations in the promoter region along with those in coding regions were associated with resistance to isoniazid and pyrazinamide respectively. In summary, the DRAGdb database is a compilation of all the major MTB drug resistance genes across bacterial species, which allows identification of homoplasy and pleiotropy phenomena of DRAGs.
Highlights
There is a rise in the use of broad spectrum antibiotics such as rifamycins, aminoglycosides and fluoroquinolones against tuberculosis (TB), as well as common bacterial infections such as gastro-intestinal infections[1,2,3]
In order to facilitate the characterization of mutations in Drug Resistance Associated Genes (DRAGs) across bacterial species, we present Drug Resistance Associated Genes database (DRAGdb), a manually curated database that has enlisted DRAG mutations across bacterial communities focusing on drugs used to treat tuberculosis
The PROVEAN scores predicting the functionality of gene-mutations in different bacteria were added in DRAGdb and the full list of each entry is available in Supplementary File
Summary
There is a rise in the use of broad spectrum antibiotics such as rifamycins, aminoglycosides and fluoroquinolones against tuberculosis (TB), as well as common bacterial infections such as gastro-intestinal infections[1,2,3]. DRAGdb provides mutation information related to 6 drugs, a few of which are broad spectrum antibiotics and 12 associated genes across bacterial species including MTB, ESKAPE and other pathogens such as Escherichia coli and Salmonella enterica. It provides drug resistance patterns of non-pathogenic bacteria including Staphylococcus epidermidis and Bifidobacterium species[24,25]. Homoplasy is described as a phylogenetic event when a resistance determining mutation arises in phylogeny under selection pressure across species or strains[27] Another major phylogenetic event occurs when a resistance determining mutation causes pleiotropic effects on resistance to other drugs in a bacteria due to resistance selection[28]. DRAGdb is a manually curated database of drug resistant genes of bacteria with a focus on TB drugs, which reveals that at least 6 genes carry drug resistance mutations across bacterial species, whereas some drug resistance genes are specific to Mycobacterium species
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