Mutations associated with in vitro resistance to bedaquiline in Mycobacterium tuberculosis isolates in Australia

Martínez, Elena; Hennessy, Daneeta; Jelfs, Peter; Crighton, Taryn; Chen, Sharon C‐A; Sintchenko, Vitali

doi:10.1016/j.tube.2018.04.007

Cited by 32 publications

(31 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In agreement with the in vitro MIC experiments, the in silico structural analysis on the Rv0678 single monomer protein form (PDB 4N5B) showed that mutations Met111Lys and Arg96Trp have very high Eris and MAESTRO ΔΔG Kcal/mol energy values, indicating a strong destabilization of the protein folding. The mutations Gly87Arg and Leu117Arg in Rv0678 were previously described in BDQ-susceptible strains ( 13 ), confirming the detected low MIC of 0.03 µg/ml and 0.12 µg/ml, respectively. (Dataset S1).…”

Section: Discussionsupporting

confidence: 78%

“…However, our phenotypic and in silico results suggest that Leu117Arg affects the dimerization of Rv0678 causing a small increase but not high-level value of BDQ MIC. Other mutations in Rv0678 were described at the same codon position but with a different amino acid change ( 5, 8, 9, 11, 13 ). The Rv0678 mutations Val20Phe, Ala84Glu and Arg90Pro were observed to be linked to increase MICs for CLF and potentially associated to a BDQ-resistant phenotype, while Val20Gly was associated with both BDQ and CLF resistance ( 5, 9 ).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, in silico analysis confirmed that the Arg90Cys mutation can have a mild effect on protein stability and a role in the small variation of BDQ MIC. Mutations Arg96Gln, Met146Thr and Leu136Pro in Rv0678 have been described with increased MIC values for BDQ ( 8, 11, 13 ). In our dataset, strains harbouring mutations at the same codons were not consistently phenotypically resistant, with mutations Arg96Trp, Met146Arg and Leu136Val respectively showing MICs of 0.25 µg/ml (BDQ-resistant), 0.06 µg/ml (BDQ-susceptible) and 0.03 µg/ml (BDQ-susceptible).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that MDR/XDR-TB patients treated with BDQ and DLM rapidly develop resistance due to fixed mutations in candidate genes which often appear as previously undescribed novel variants ( 3, 4, 5, 6, 7 ). Additionally, resistance to BDQ can arise in naïve populations of MTBc strains as a consequence of a clofazimine-containing regimen, or by random mutations affecting the drug targets ( 8, 9, 10, 11, 12, 13, 14 ). DLM resistance not associated to exposure has been reported as well ( 15, 16, 17, 18, 19 ).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Characterization of genomic variants associated with resistance to bedaquiline and delamanid in naïve Mycobacterium tuberculosis clinical strains

Battaglia¹,

Spitaleri

Cabibbe³

et al. 2020

Preprint

View full text Add to dashboard Cite

The role of genetic mutations in genes associated to phenotypic resistance to bedaquiline (BDQ) and delamanid (DLM) in Mycobacterium tuberculosis complex (MTBc) strains is poorly understood. However, a clear understanding of the role of each genetic variant is crucial to guide the development of molecular-based drug susceptibility testing (DST). In this work, we analysed all mutations in candidate genomic regions associated with BDQ- and DLM-resistant phenotypes using a whole genome sequencing (WGS) dataset from a collection of 4795 MTBc clinical isolates from six high-burden countries of tuberculosis (TB). From WGS analysis, we identified 61 and 158 unique mutations in genomic regions potentially involved in BDQ- and DLM-resistant phenotypes, respectively. Importantly, all strains were isolated from patients who likely have never been exposed to the medicines. In order to characterize the role of mutations, we performed an energetic in silico analysis to evaluate their effect in the available protein structures Ddn (DLM), Fgd1 (DLM) and Rv0678 (BDQ), and minimum inhibitory concentration (MIC) assays on a subset of MTBc strains carrying mutations to assess their phenotypic effect. The combination of structural protein information and phenotypic data allowed for cataloging the mutations clearly associated with resistance to BDQ (n= 4) and DLM (n= 35), as well as about a hundred genetic variants without any correlation with resistance. Importantly, these results show that both BDQ and DLM resistance-related mutations are diverse and distributed across the entire region of each gene target, which is of critical importance to the development of comprehensive molecular diagnostic tools.ImportancePhenotypic drug susceptibility tests (DST) are too slow to provide an early indication of drug susceptibility status at the time of treatment initiation and very demanding in terms of specimens handling and biosafety. The development of molecular assays to detect resistance to bedaquiline (BDQ) and delamanid (DLM) requires accurate categorization of genetic variants according to their association with phenotypic resistance. We have evaluated a large multi-country set of clinical isolates to identify mutations associated with increased minimum inhibitory concentrations (MICs) and used an in silico protein structure analysis to further unravel the potential role of these mutations in drug resistance mechanisms. The results of this study are an important source of information for the development of molecular diagnostic tests to improve the provision of appropriate treatment and care to TB patients.

show abstract

Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Characterization of genomic variants associated with resistance to bedaquiline and delamanid in naïve Mycobacterium tuberculosis clinical strains

Battaglia¹,

Spitaleri

Cabibbe³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Eight publications presented longitudinal studies where BDQ or DLM resistance was developed after (in vivo or in vitro) drug exposure [5,6,[25][26][27][28][29][30]. Some of these longitudinal studies evaluated two to eight isolates from the same patient.…”

Section: Description Of Collected Articlesmentioning

confidence: 99%

Whole Genome Sequencing for the Analysis of Drug Resistant Strains of Mycobacterium tuberculosis: A Systematic Review for Bedaquiline and Delamanid

2020

View full text Add to dashboard Cite

Tuberculosis (TB) remains the deadliest Infectious disease worldwide, partially due to the increasing dissemination of multidrug and extensively drug-resistant (MDR/XDR) strains. Drug regimens containing the new anti-TB drugs bedaquiline (BDQ) and delamanid (DLM) appear as a last resort for the treatment of MDR or XDR-TB. Unfortunately, resistant cases to these drugs emerged just one year after their introduction in clinical practice. Early detection of resistant strains to BDQ and DLM is crucial to preserving the effectiveness of these drugs. Here, we present a systematic review aiming to define all available genotypic variants linked to different levels of resistance to BDQ and DLM that have been described through whole genomic sequencing (WGS) and the available drug susceptibility testing methods. During the review, we performed a thorough analysis of 18 articles. BDQ resistance was associated with genetic variants in Rv0678 and atpE, while mutations in pepQ were linked to a low-level of resistance for BDQ. For DLM, mutations in the genes ddn, fgd1, fbiA, and fbiC were found in phenotypically resistant cases, while all the mutations in fbiB were reported only in DLM-susceptible strains. Additionally, WGS analysis allowed the detection of heteroresistance to both drugs. In conclusion, we present a comprehensive panel of gene mutations linked to different levels of drug resistance to BDQ and DLM.

show abstract

Molecular Basis of Drug Resistance in Mycobacteria

Katoch

2019

Pathogenicity and Drug Resistance of Human Pathogens

View full text Add to dashboard Cite

Mutations associated with in vitro resistance to bedaquiline in Mycobacterium tuberculosis isolates in Australia

Cited by 32 publications

References 12 publications

Characterization of genomic variants associated with resistance to bedaquiline and delamanid in naïve Mycobacterium tuberculosis clinical strains

Characterization of genomic variants associated with resistance to bedaquiline and delamanid in naïve Mycobacterium tuberculosis clinical strains

Whole Genome Sequencing for the Analysis of Drug Resistant Strains of Mycobacterium tuberculosis: A Systematic Review for Bedaquiline and Delamanid

Molecular Basis of Drug Resistance in Mycobacteria

Contact Info

Product

Resources

About