Structure-Aware Mycobacterium tuberculosis Functional Annotation Uncloaks Resistance, Metabolic, and Virulence Genes

Modlin, Samuel J; Elghraoui, Afif; Gunasekaran, Deepika; Zlotnicki, Alyssa M.; Dillon, Nicholas; Dhillon, Nermeeta; Kuo, Norman; Robinhold, Cassidy; Chan, Carmela K.; Baughn, Anthony D.; Valafar, Faramarz

doi:10.1128/msystems.00673-21

Cited by 6 publications

(4 citation statements)

References 128 publications

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“…Rv1359 and the upstream gene, Rv1358, on the opposite strand are very similar to each other (43.7% identity in 197 aa overlap) and to another gene elsewhere in the genome, Rv0891c (48.5% identity in 204 aa overlap) (Kapopoulou et al, 2011). All three genes are possible LuxR family transcriptional regulators, which are thought to be involved in quorum‐sensing adaptations and contain a probable ATP/GTP binding site motif (Chen & Xie, 2011; Modlin et al, 2021) and are found in different modules. Expression of this antisense sRNA appears to suppress the expression of the transcript on the opposite strand to varying degrees in all conditions (Figure 7).…”

Section: Resultsmentioning

confidence: 99%

Using a whole genome co‐expression network to inform the functional characterisation of predicted genomic elements from Mycobacterium tuberculosis transcriptomic data

Stiens

Tan

Joyce

et al. 2023

Molecular Microbiology

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A whole genome co-expression network was created using Mycobacterium tuberculosis transcriptomic data from publicly available RNA-sequencing experiments covering a wide variety of experimental conditions. The network includes expressed regions with no formal annotation, including putative short RNAs and untranslated regions of expressed transcripts, along with the protein-coding genes. These unannotated expressed transcripts were among the best-connected members of the module sub-networks, making up more than half of the 'hub' elements in modules that include protein-coding genes known to be part of regulatory systems involved in stress response and host adaptation.This dataset provides a valuable resource for investigating the role of non-coding RNA, and conserved hypothetical proteins, in transcriptomic remodelling. Based on their connections to genes with known functional groupings and correlations with replicated host conditions, predicted expressed transcripts can be screened as suitable candidates for further experimental validation. Non-coding RNA prediction and quantificationEach dataset was run through the R-package, baerhunter (Ozuna et al., 2019), using the 'feature_file_editor' function optimised to the most appropriate parameters for the sequencing depth (https://doi.org/10.5281/zenodo.7709329). 'Count_features' and 'tpm_norm_flagging' functions were used for transcript quantification and to identify low

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Section: Resultsmentioning

confidence: 99%

Using a whole genome co‐expression network to inform the functional characterisation of predicted genomic elements from Mycobacterium tuberculosis transcriptomic data

Stiens

Tan

Joyce

et al. 2023

Molecular Microbiology

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“…Consistent with other recent studies ( 20 – 22 , 32 – 34 ), insertions were identified in the carboxy-terminal coding region of panD and in the promoter region of clpC1 ( Table S2 ). Eight additional unique insertions were identified within seven other genes ( Table S2 ), four of which we recently associated with PZA or POA resistance ( 35 ). These strains showed 2- to 16-fold resistance to POA at pH 6.6 (MIC, 400 to 3,200 μg mL −1 ), whereas PZA resistance was typically only 2-fold at pH 5.8 (MIC, 100 μg mL −1 ) relative to the parental strain ( Table S2 ), as was previously described for panD and clpC1 mutant strains ( 32 ).…”

Section: Resultsmentioning

confidence: 99%

Pyrazinamide Susceptibility Is Driven by Activation of the SigE-Dependent Cell Envelope Stress Response in Mycobacterium tuberculosis

Thiede

Dillon

Howe

et al. 2022

mBio

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“…This is consistent with another study, where adenylyl- or CoA-transferase activity was shown for Rv0036c [ 56 ]. Structural analysis infers that Rv0036c protein is a mycothiol-dependent metalloenzyme with possible dinB-like activity [ 57 ]. DinB is a DNA polymerase IV, which confers a mutator phenotype to the cell when the gene product is overexpressed [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Study of Drug Resistant Mycobacterium tuberculosis and Its Intra-Host Evolution during Treatment

et al. 2022

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The emergence of drug resistant Mycobacterium tuberculosis (MTB) strains has become a global public health problem, while, at the same time, there has been development of new antimicrobial agents. The main goals of this study were to determine new variants associated with drug resistance in MTB and to observe which polymorphisms emerge in MTB genomes after anti-tuberculosis treatment. We performed whole-genome sequencing of 152 MTB isolates including 70 isolates as 32 series of pre- and post-treatment MTB. Based on genotypes and phenotypic drug susceptibility, we conducted phylogenetic convergence-based genome-wide association study (GWAS) with streptomycin-, isoniazid-, rifampicin-, ethambutol-, fluoroquinolones-, and aminoglycosides-resistant MTB against susceptible ones. GWAS revealed statistically significant associations of SNPs within Rv2820c, cyp123 and indels in Rv1269c, Rv1907c, Rv1883c, Rv2407, Rv3785 genes with resistant MTB phenotypes. Comparisons of serial isolates showed that treatment induced different patterns of intra-host evolution. We found indels within Rv1435c and ppsA that were not lineage-specific. In addition, Beijing-specific polymorphisms within Rv0036c, Rv0678, Rv3433c, and dop genes were detected in post-treatment isolates. The appearance of Rv3785 frameshift insertion in 2 post-treatment strains compared to pre-treatment was also observed. We propose that the insertion within Rv3785, which was a GWAS hit, might affect cell wall biosynthesis and probably mediates a compensatory mechanism in response to treatment. These results may shed light on the mechanisms of MTB adaptation to chemotherapy and drug resistance formation.

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Structure-Aware Mycobacterium tuberculosis Functional Annotation Uncloaks Resistance, Metabolic, and Virulence Genes

Cited by 6 publications

References 128 publications

Using a whole genome co‐expression network to inform the functional characterisation of predicted genomic elements from Mycobacterium tuberculosis transcriptomic data

Using a whole genome co‐expression network to inform the functional characterisation of predicted genomic elements from Mycobacterium tuberculosis transcriptomic data

Pyrazinamide Susceptibility Is Driven by Activation of the SigE-Dependent Cell Envelope Stress Response in Mycobacterium tuberculosis

Genome-Wide Study of Drug Resistant Mycobacterium tuberculosis and Its Intra-Host Evolution during Treatment

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