Acquisition of Cross-Resistance to Bedaquiline and Clofazimine following Treatment for Tuberculosis in Pakistan

Ghodousi, Arash; Rizvi, Alamdar Hussain; Baloch, Aurangzaib Quadir; Ghafoor, Abdul; Khanzada, Faisal Masood; Qadir, Mehmood; Borroni, Emanuele; Trovato, Alberto; Tahseen, Sabira; Cirillo, Daniela María

doi:10.4103/2212-5531.307111

Cited by 3 publications

(3 citation statements)

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“…In this study, we focused on structural mechanisms of Rv0678 mediated resistance, as these mutations are the most clinically relevant and correlated with BDQ treatment failures. Other genes which have been linked to BDQ or CFZ resistance, such as atpE, pepQ and Rv1979c, but their clinical relevance has yet to be established 10,29,68,69 . In the CRyPTIC dataset we identified four Rv1979c variants which presented a resistant phenotype to BDQ with variable CFZ cross resistance, and seven mutations in pepQ garnering borderline BDQ resistance and variable CFZ resistance.…”

Section: Wt Visualization From Top Wt Visualization From Bottom L40v (S) Visualization From Bottom L40f (R) Visualization From Bottom A10mentioning

confidence: 99%

Deciphering Bedaquiline and Clofazimine Resistance in Tuberculosis: An Evolutionary Medicine Approach

Sonnenkalb

Carter

Spitaleri

et al. 2021

Preprint

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Bedaquiline (BDQ) and clofazimine (CFZ) are core drugs for treatment of multidrug resistant tuberculosis (MDR-TB), however, our understanding of the resistance mechanisms for these drugs is sparse which is hampering rapid molecular diagnostics. To address this, we employed a unique approach using experimental evolution, protein modelling, genome sequencing, and minimum inhibitory concentration data (MIC) combined with genomes from a global strain collection of over 14,151 Mycobacterium tuberculosis complex isolates. Overall, 189 genomic variants causing elevated BDQ and/or CFZ MICs could be discerned, with 175 (95.1%) variants affecting the transcriptional repressor (Rv0678) of an efflux system (MmpS5-MmpL5). Structural modelling of Rv0678 suggests four major mechanisms that confer resistance: impairment of DNA binding, reduction in protein stability, disruption of protein dimerization, and reduction in affinity for its fatty acid ligand. These modelling and experimental techniques will improve personalized medicine in an impending drug resistant era.

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Section: Wt Visualization From Top Wt Visualization From Bottom L40v (S) Visualization From Bottom L40f (R) Visualization From Bottom A10mentioning

confidence: 99%

Deciphering Bedaquiline and Clofazimine Resistance in Tuberculosis: An Evolutionary Medicine Approach

Sonnenkalb

Carter

Spitaleri

et al. 2021

Preprint

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“…Rv1978, another of the 10 genes in RD2, and located in the region Rv1977-Rv1978-Rv1979c was absent in the 3 complete (PacBio-sequenced) genomes of L5 strains, but present in 2 L5 strains Illumina-sequenced genomes [2/202, 1 %; further confirmed using blast search and manual check of the gene in the reads of the 2 L5 strains genomes (ERR439931 and ERR4192386)], making up the region containing Rv1977, Rv1978 and Rv1979c, a region absent in most of L5 strains (99 %, 200/202). Rv1979c has been associated with clofazimine and bedaquiline resistance [70,71], two of the drugs used for the treatment of rifampicin-and multidrug-resistant TB [72,73], but minimal inhibitory concentration testing of clofazimine in five L5 strains did not find that the deletion conferred resistance [74]. Further studies and protein function discovery is needed to investigate the consequences of the absence of those genes in genomes of L5 strains.…”

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confidence: 99%

Mycobacterium tuberculosis complex lineage 5 exhibits high levels of within-lineage genomic diversity and differing gene content compared to the type strain H37Rv

et al. 2021

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Pathogens of the Mycobacterium tuberculosis complex (MTBC) are considered to be monomorphic, with little gene content variation between strains. Nevertheless, several genotypic and phenotypic factors separate strains of the different MTBC lineages (L), especially L5 and L6 (traditionally termed Mycobacterium africanum ) strains, from each other. However, this genome variability and gene content, especially of L5 strains, has not been fully explored and may be important for pathobiology and current approaches for genomic analysis of MTBC strains, including transmission studies. By comparing the genomes of 355 L5 clinical strains (including 3 complete genomes and 352 Illumina whole-genome sequenced isolates) to each other and to H37Rv, we identified multiple genes that were differentially present or absent between H37Rv and L5 strains. Additionally, considerable gene content variability was found across L5 strains, including a split in the L5.3 sub-lineage into L5.3.1 and L5.3.2. These gene content differences had a small knock-on effect on transmission cluster estimation, with clustering rates influenced by the selected reference genome, and with potential overestimation of recent transmission when using H37Rv as the reference genome. We conclude that full capture of the gene diversity, especially high-resolution outbreak analysis, requires a variation of the single H37Rv-centric reference genome mapping approach currently used in most whole-genome sequencing data analysis pipelines. Moreover, the high within-lineage gene content variability suggests that the pan-genome of M. tuberculosis is at least several kilobases larger than previously thought, implying that a concatenated or reference-free genome assembly (de novo) approach may be needed for particular questions.

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“…Although its mechanism is not fully understood, delamanid is thought to undergo reductive activation by mycobacterial deazaflavin‐dependent nitroreductase to form a radical intermediate that inhibits methoxymycolic acid and ketomycolic acid formation (Gurumurthy et al, 2012). One of prominent reported side effect of bedaquiline includes cardiac toxicity (Pontali et al, 2017) while delamanid induces prolongation of QTc (Guglielmetti et al, 2018); (Pontali et al, 2017) Cross‐resistance between bedaquiline and clofazimine has also been reported (Ghodousi et al, 2019; Xu et al, 2017). Renewed effort towards the discovery of new targets and anti‐tubercular agents has led to the advancement of other drug candidates to the clinical developmental stage (Fernandes et al, 2017; Mdluli et al, 2015), including SQ109, moxifloxacin, Q20321 and sutezolid (Li et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

A consequence of drug targeting of aminoacyl‐tRNA synthetases in Mycobacteriumtuberculosis

2021

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Drug‐resistant Mycobacterium tuberculosis poses a great threat to public health and remains one of the red‐flag tagged infectious diseases, with the tendency of comorbidity with other disease conditions such as HIV/AIDS. This perhaps is responsible for redoubling of effort in tuberculosis research and continuous change in patient management to optimize the drug therapy. Aminoacyl‐tRNA synthetases are essential enzymes in M. tuberculosis that catalyse the transfer of a particular amino acid to its corresponding specific tRNA to form an aminoacyl‐tRNA. These enzymes are believed to be novel antibacterial, antifungal and antiparasitic drug targets because of their role in the process of protein translation. Therefore, their existence as a compliment of M. tuberculosis has attracted a lot of research interest with the aim of curbing the scourge and provide the most effective drug in the treatment of tuberculosis. This leads to the discovery of a pool of aminoacyl‐tRNA synthetases with their essential inhibitors. This review seeks to articulate the current advances in the development of new TB drugs exhibiting novelty in their mode of action with specific emphasis on aminoacyl‐tRNA synthetases as drug targets.

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Acquisition of Cross-Resistance to Bedaquiline and Clofazimine following Treatment for Tuberculosis in Pakistan

Cited by 3 publications

References 0 publications

Deciphering Bedaquiline and Clofazimine Resistance in Tuberculosis: An Evolutionary Medicine Approach

Deciphering Bedaquiline and Clofazimine Resistance in Tuberculosis: An Evolutionary Medicine Approach

Mycobacterium tuberculosis complex lineage 5 exhibits high levels of within-lineage genomic diversity and differing gene content compared to the type strain H37Rv

A consequence of drug targeting of aminoacyl‐tRNA synthetases in Mycobacteriumtuberculosis

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