Molecular mechanisms of action, resistance, detection to the first-line anti tuberculosis drugs: Rifampicin and pyrazinamide in the post whole genome sequencing era

Unissa, Ameeruddin Nusrath; Hanna, Luke Elizabeth

doi:10.1016/j.tube.2017.04.008

Cited by 38 publications

(15 citation statements)

References 105 publications

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“…Surprisingly, all five patients confirmed to have RR-TB based on the results of the repeated MGIT tests also harbored disputed mutations ( Table 1). We speculate that phenotypic resistance in these five isolates was not solely determined by these disputed mutations, and other genomic variants or transcriptional alterations may have caused low levels of RIF resistance (38,39). The reason why initial phenotypic DST testing gave RIF susceptible results for these five patients is unclear but may have been due to laboratory error when performing the phenotypic DST (37), particularly in the case of the patient whose isolate harbored a His526Arg mutation and had a MIC of 64 g/ml.…”

Section: Discussionmentioning

confidence: 94%

Retrospective Analysis of False-Positive and Disputed Rifampin Resistance Xpert MTB/RIF Assay Results in Clinical Samples from a Referral Hospital in Hunan, China

Zhang

Fleming

et al. 2019

J Clin Microbiol

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Concerns about the specificity of the Xpert MTB/RIF (Xpert) assay have arisen, as false-positive errors in the determination of Mycobacterium tuberculosis complex (MTBC) infection and rifampin (RIF) resistance in clinical practice have been reported. Here, we investigated 33 cases where patients were determined to be RIF susceptible using the Bactec MGIT 960 (MGIT) culture system but RIF resistant using the Xpert assay. Isolates from two of these patients were found not to have any mutations in the rifampin resistance determining region (RRDR) region of rpoB and had good treatment outcomes with first-line antituberculosis (anti-TB) drugs. The remaining 31 patients included 5 new cases and 26 previously treated patients. A large number of well-documented disputed mutations, including Leu511Pro, Asp516Tyr, His526Asn, His526Leu, His526Cys, and Leu533Pro, were detected, and mutations, including a 508 to 509 deletion and His526Gly, were described here as disputed mutations for the first time. Twenty-one (81%) of the 26 previously treated patients had poor treatment outcomes, and isolates from 19 (90%) of these 21 patients were resistant to isoniazid (INH) as determined using the MGIT culture system. Twenty-seven of the 31 isolates with disputed rpoB mutations were phenotypically resistant to INH, 21 (78%) being predicted by GenoType MTBDRplus to have a high level of INH resistance. Most (77.4%) of the isolates with disputed mutations were of the Beijing lineage. These findings have implications for the interpretation of false-positive and disputed rifampin resistance Xpert MTB/RIF results in clinical samples and provide guidance on how clinicians should manage patients carrying isolates with disputed rpoB mutations.

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Section: Discussionmentioning

confidence: 94%

Retrospective Analysis of False-Positive and Disputed Rifampin Resistance Xpert MTB/RIF Assay Results in Clinical Samples from a Referral Hospital in Hunan, China

Zhang

Fleming

et al. 2019

J Clin Microbiol

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“…Mutations in the core subunits of RNAP emerge in response to diverse selection pressures, including of course selection by antibiotics that target RNAP directly. For example, rifampicin resistance mutations, which are of clinical relevance in M. tuberculosis , often map to rpoB (Goldstein, ), and may then lead to compensatory changes in other subunits (Brandis et al , ; Nusrath Unissa and Hanna, ). Mutations in RNA polymerase may also arise that increase or decrease the activity of regulatory proteins.…”

Section: Discussionmentioning

confidence: 99%

Deciphering the essentiality and function of the anti‐σ^M factors in Bacillus subtilis

Zhao

Roistacher

Helmann

2019

Molecular Microbiology

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Bacteria use alternative sigma factors to adapt to different growth and stress conditions. The Bacillus subtilis extracytoplasmic function sigma factor SigM regulates genes for cell wall synthesis and is crucial for maintaining cell wall homeostasis under stress conditions. The activity of SigM is regulated by its anti-sigma factor, YhdL, and the accessory protein YhdK. Here, we show that dysregulation of SigM caused by the absence of either component of the anti-sigma factor complex leads to toxic levels of SigM and severe growth defects. High SigM activity results from a dysregulated positive feedback loop, and can be suppressed by overexpression of the housekeeping sigma, SigA. Using a sigM merodiploid strain, we selected for suppressor mutations that allow survival of yhdL depletion strain. The recovered suppressor mutations map to the beta and beta-prime subunits of RNA polymerase core enzyme and selectively reduce SigM activity, and in some cases increase the activity of other alternative sigma factors. This work highlights the ability of mutations in RNA polymerase that remodel the sigma-core interface to differentially affect sigma factor activity, and thereby alter the transcriptional landscape of the cell.

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“…PZA is a key first-line drug that kills subpopulations of non-replicated MTB. Previous studies reported that resistance to PZA develops due to mutations in pncA , but resistance may also develop due to mutations in ribosomal protein S1 (RpsA) and aspartate decarboxylase ( panD ) genes [ 8 , [35] , [36] , [37] ]. In our recent study, we reported some novel mutations in the RpsA gene present in PZA resistance isolates from Khyber Pakhtunkhwa, Pakistan, but the molecular mechanism behind these mutants is still to be explored.…”

Section: Discussionmentioning

confidence: 99%

Insight into novel clinical mutants of RpsA-S324F, E325K, and G341R of Mycobacterium tuberculosis associated with pyrazinamide resistance

Khan

Rehaman

Junaid

et al. 2018

Computational and Structural Biotechnology Journal

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Pyrazinamide (PZA) is an important component of first-line anti-tuberculosis drugs which is converted into active form, pyrazinoic acid (POA), by Mycobacterium tuberculosis (MTB) pncA gene encoded, pyrazinamidase (PZase). Mutations in pncA are detected in >70% of PZA resistant isolates but, noticeably, not in all. In this study, we selected 18 PZA-resistant but wild type pncA (pncAWT) MTB isolates. Drug susceptibility testing (DST) of all the isolates were repeated at the critical concentration of PZA drug. All these PZA-resistance but pncAWT isolates were subjected to RpsA sequencing. Fifteen different mutations were identified in eleven isolates, where seven were present in a conserved region including, Ser324Phe, Glu325Lys, Gly341Arg. As the molecular mechanism of resistance behind these variants has not been reported earlier, we have performed multiple analysis to unveil the mechanisms of resistance behind mutations S324F, E325K, and G341R. The mutant and wild type RpsA structures were subjected to comprehensive computational molecular dynamic simulations at 50 ns. Root mean square deviation (RMSD), Root mean square fluctuation (RMSF), and Gibbs free energy of mutants were analyzed in comparison with wild type. Docking score of wild type-RpsA has been found to be maximum, showing a strong binding affinity in comparison with mutants. Pocket volume, RMSD and RMSF have also been found to be altered, whereas total energy, folding effect (radius of gyration) and shape complimentarily analysis showed that variants S324F, E325K, and G341R have been playing a significant role behind PZA-resistance. The study offers valuable information for better management of drug resistance tuberculosis.

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Molecular mechanisms of action, resistance, detection to the first-line anti tuberculosis drugs: Rifampicin and pyrazinamide in the post whole genome sequencing era

Cited by 38 publications

References 105 publications

Retrospective Analysis of False-Positive and Disputed Rifampin Resistance Xpert MTB/RIF Assay Results in Clinical Samples from a Referral Hospital in Hunan, China

Retrospective Analysis of False-Positive and Disputed Rifampin Resistance Xpert MTB/RIF Assay Results in Clinical Samples from a Referral Hospital in Hunan, China

Deciphering the essentiality and function of the anti‐σ^M factors in Bacillus subtilis

Insight into novel clinical mutants of RpsA-S324F, E325K, and G341R of Mycobacterium tuberculosis associated with pyrazinamide resistance

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Molecular mechanisms of action, resistance, detection to the first-line anti tuberculosis drugs: Rifampicin and pyrazinamide in the post whole genome sequencing era

Cited by 38 publications

References 105 publications

Retrospective Analysis of False-Positive and Disputed Rifampin Resistance Xpert MTB/RIF Assay Results in Clinical Samples from a Referral Hospital in Hunan, China

Retrospective Analysis of False-Positive and Disputed Rifampin Resistance Xpert MTB/RIF Assay Results in Clinical Samples from a Referral Hospital in Hunan, China

Deciphering the essentiality and function of the anti‐σM factors in Bacillus subtilis

Insight into novel clinical mutants of RpsA-S324F, E325K, and G341R of Mycobacterium tuberculosis associated with pyrazinamide resistance

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Product

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Deciphering the essentiality and function of the anti‐σ^M factors in Bacillus subtilis