(a) Geographical distribution of 2773 clinical strains of Mycobacterium tuberculosis (Mtb). The donut plot represents the proportion of susceptible and drug-resistant (DR) strains in each lineage. …
Each donut plot represents proportion of clinical strains used for the genome-wide association study. Susceptible refers to the antibiotic sensitive strains. DR refers to ‘drug resistance’ to first- …
(a) Volcano plot represents the effect of identified single nucleotide polymorphisms (SNPs) on the development of multidrug resistant/extensively drug resistant TB (MDR/XDR-TB). The positive effect …
Mutations identified in genes that belong to different categories.
Bar graph representing the (a) heterozygosity of strains, (b) heterozygosity of markers, and (c) frequency and accumulative frequency of marker density.
(a) Linkage disequilibrium decay over distance. (b) Minor allele frequency (MAF). (c) Quantile-quantile – plot of p-values.
(a–d) Density of markers.
(a) The profile for the optimum compression. (b) Type-I error plot.
In the natural process of evolution, host-imposed stress and antibiotic treatment result in the evolution of wild-type bacteria to multidrug resistant/extensively drug resistant (MDR/XDR). However, …
(a–d) Distribution plot showing single nucleotide polymorphisms (SNPs) in mutY, recF, uvrA, and uvrB identified in drug-resistant strains. Wild type and the alternative alleles are shown. (e–h) …
(a) A schematic representation of the base excision repair pathway that operates in mycobacteria. Oxidative damage can result in the conversion of G to 8-oxo-G. If MutM (Fpg) does not repair 8-oxo-G …
Mutation rate analysis in the presence of different drugs.
(a) Manhattan plot showing identifying genes that belong to DNA repair and direct target of antibiotics. (b) Schematic depicting the generation of gene replacement mutant of mutY. The hygromycinr …
Confirmation of gene repalcement mutant and complementation strains.
(a) Mutation frequency was calculated for different strains in the presence of rifampicin (a) or isoniazid (b). (c) Table showing the fold increase in the mutation frequency in comparison with …
Analysis of Mutation frequency.
(a) Schematic representation of killing kinetics. (b) Growth kinetics in the absence of drugs. (c–f) Growth kinetics in the presence of isoniazid, rifampicin, ciprofloxacin, and ethambutol. Two …
Killing kinetics in the absence and presence of different antibiotics.
(a) A schematic is representing the ex vivo infection experiment in the presence and absence of different antibiotics. (b–e) Survival of the strains in the peritoneal macrophages at 4 and 96 hr …
Survival of different strains in the absence and presence of antibiotics ex vivo.
(a) Survival of strains with respect to 4 hr post-infection (p.i.) in peritoneal macrophages. (b) CFU enumeration of strains at 4 and 96 hr p.i. (c) Percent survival of each strain in the …
Survival of strains before and after passage in the peritoneal macrophages.
(a–d) Circos plot showing the WGS analysis of the strains passaged ex vivo in the absence (a) and in the presence of isoniazid (b), rifampicin (c), and ciprofloxacin (d). The outermost circle …
(a) Schematic representing the competition experiment performed in peritoneal macrophages. Strains obtained after three rounds of infection in the peritoneal macrophages were used to perform a …
Competition experiment in the presence and absence of different drugs after passage in the peritoneal macrophages.
(a) A schematic representation of the guinea pig infection experiment. (b) Gross histopathology of lungs and spleen of infected guinea pigs. (c) Hematoxylin and eosin staining of infected lung …
Gross histopathology of the infected lungs and spleen isolated from guinea pig.
Haematoxylin and eosin staining.
Survival of different strains in vivo.
Gross histopathology of lungs and spleen isolated from guinea pigs after competition experiment.
(a) Circos plot shows the WGS analysis of the strains isolated from guinea pig lungs. The outermost circle represents the reference genome labeled with the known direct target mutations. Circles …
Model depicts the analysis and subsequent validation. Genome-wide association study (GWAS) revealed mutation in three DNA repair pathway genes in multidrug resistant/extensively drug resistant …
Antibiotic | Gene | Mutations identified |
---|---|---|
Rifampicin | rpoB | Leu452Pro, Val496Meth |
Isoniazid | katG | Ser315Thr |
Ethambutol | embB | Gly406Ser |
Ofloxacin | gyrA | Ala90Val, Ser91Pro |
Kanamycin | rrs | 7 independent mutations |
Pyrazinamide | pncA | His71Arg |
Ethionamide | ethA | Met95Arg, Pro160(frame-shift) |
Streptomycin | gidB | Leu35 (frame-shift) |
Cycloserine | ald | Thr427Pro |
Gene | Amino acid change | Wild type | Mutated | False discovery rate-adjusted p-value |
---|---|---|---|---|
mutY | Arg262Gln | G | A | 3.83E-09 |
uvrB | Ala524Val | C | T | 2.15E-07 |
uvrA | Gln135Lys | C | A | 3.83E-09 |
RecF | Gly269Gly | G | T | 2.15E-07 |
Gene | False discovery rate-adjusted p-value | Variant |
---|---|---|
rv1258c | 1.60E-08 | Non-syn |
mmpL2 | 9.51E-05 | Non-syn |
rv0987 | 1.60E-08 | Non-syn |
rv1250 | 3.44E-07 | Non-syn |
kdpC | 2.15E-07 | Non-syn |
rv0928 | 2.15E-07 | Non-syn |
rv2333c | 1.32E-20 | Frameshift |
mmpL13a | 1.25E-06 | Syn |
kdpB | 2.15E-07 | Syn |
Total number of clinical strains used in this study.
The table contains the total number of clinical strains obtained from different studies.
Clinical strains used for the Genome-wide association analysis.
The table contains the clinical strains which are used for performing genome-wide association study analysis.
Synonymous change identified in the association analysis.
The table contains synonymous changes identified in the multidrug-resistant/extensively drug-resistant strains.
Non-synonymous change identified in the association analysis.
The table contains non-synonymous changes identified in the multidrug-resistant/extensively drug-resistant strains.
Upstream gene variants identified in the association analysis.
The table contains non-upstream gene variants identified in the multidrug-resistant/extensively drug-resistant strains.
Stop codon or frameshift mutations identified in the association analysis.
The table contains Stop codon or frameshift mutations identified in the multidrug-resistant/extensively drug-resistant strains.
Codon usage of the multidrug-resistant/extensively drug-resistant (MDR/XDR) strains.
The table contains codon usage in the MDR/XDR and Rv strain.
Mutations identified in Rv, RvΔmutY, RvΔmutY::mutY, and RvΔmutY::mutY-R262Q strains under different conditions.
The table consists of percentage of mutation and blosum score of genes that harbor s under different conditions.
Oligonucleotide used in the study.
The table consists of oligonucleotide used in the study.