Reduced susceptibility and resistance to bedaquiline in clinical M. tuberculosis isolates

Peretokina, Irina V.; Krylova, L. Yu.; Антонова, О. В.; Kholina, Margarita S.; Kulagina, Elena V.; Nosova, Elena; Safonova, Svetlana; Borisov, Sergey; Zimenkov, Danila

doi:10.1016/j.jinf.2020.01.007

Cited by 39 publications

(48 citation statements)

References 45 publications

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“…This is likely a function of the low frequency of viable spontaneous atpE mutants and their fitness costs observed in vivo (31). Although atpE mutations have been identified in a small number of BDQ-resistant clinical isolates to date (32, 33), Rv0678 mutations have been more prevalent. Therefore, overcoming Rv0678 -mediated resistance with more potent diarylquinolines like TBAJ-587 could greatly extend the utility and longevity of this important new class of drugs.…”

Section: Discussionmentioning

confidence: 99%

“…Although atpE mutations have been identified in a small number of BDQ-resistant clinical isolates to date(32,33), Rv0678 mutations have been more prevalent. Therefore, overcoming Rv0678-mediated resistance with more potent diarylquinolines like TBAJ-587 could greatly extend the utility and longevity of this important new class of drugs.Use of TBAJ-587 in place of BDQ in the BPaL regimen in mice infected with the Rv0678 mutant also largely prevented the selection of spontaneous PMD-resistant double mutants.Following two months of treatment, all five BPaL-treated mice harbored dual BDQ/PMDresistant isolates, compared with zero of ten SPaL-treated mice.…”

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confidence: 99%

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Comparative efficacy of the novel diarylquinoline TBAJ-587 and bedaquiline against a resistantRv0678mutant in a mouse model of tuberculosis

Converse

Upton

et al. 2020

Preprint

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Since its conditional approval in 2012, bedaquiline (BDQ) has been a valuable tool for treatment of drug-resistant tuberculosis. More recently, a novel short-course regimen combining BDQ with pretomanid and linezolid won approval to treat highly drug-resistant tuberculosis. Clinical reports of emerging BDQ resistance have identified mutations in Rv0678 that de-repress the expression of the MmpL5/MmpS5 efflux transporter as the most common cause. Because the effect of these mutations on bacterial susceptibility to BDQ is relatively small (e.g., 2-8× MIC shift), increasing the BDQ dose would increase antibacterial activity but also pose potential safety concerns, including QTc prolongation. Substitution of BDQ with another diarylquinoline with superior potency and/or safety has the potential to overcome these limitations. TBAJ-587 has greater in vitro potency than BDQ, including against Rv0678 mutants, and may offer a larger safety margin. Using a mouse model of tuberculosis and different doses of BDQ and TBAJ-587, we found that against wild-type M. tuberculosis H37Rv and an isogenic Rv0678 mutant, TBAJ-587 has greater efficacy against both strains than BDQ, whether alone or in combination with pretomanid and either linezolid or moxifloxacin and pyrazinamide. TBAJ-587 also reduced the emergence of resistance to diarylquinolines and pretomanid.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Comparative efficacy of the novel diarylquinoline TBAJ-587 and bedaquiline against a resistantRv0678mutant in a mouse model of tuberculosis

Converse

Upton

et al. 2020

Preprint

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“…2 ). Of those, insG in the HP nt192-198, which had been repeatedly demonstrated to confer BDQ and CFZ resistance during in vitro selection experiments and patient treatment, occurred in 82 isolates, whereas the other two double mutations were observed in only a single isolate, respectively (Andres et al, 2020; de Vos et al, 2019; Ghodousi et al, 2019; Peretokina et al, 2020; Sonnenkalb et al, 2021; Zhang et al, 2015). All of the former 82 double-LoF mutants belonged to a monophyletic group within sub-lineage 4.11 that was mostly multi-drug resistant (53 of 59 with known phenotypic data).…”

Section: Resultsmentioning

confidence: 99%

The role of epistasis in amikacin, kanamycin, bedaquiline, and clofazimine resistance inMycobacterium tuberculosiscomplex

Vargas

Freschi

Spitaleri

et al. 2021

Preprint

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Antibiotic resistance among bacterial pathogens poses a major global health threat. M. tuberculosis complex (MTBC) is estimated to have the highest resistance rates of any pathogen globally. Given the slow growth rate and the need for a biosafety level 3 laboratory, the only realistic avenue to scale up drug-susceptibility testing (DST) for this pathogen is to rely on genotypic techniques. This raises the fundamental question of whether a mutation is a reliable surrogate for phenotypic resistance or whether the presence of a second mutation can completely counteract its effect, resulting in major diagnostic errors (i.e. systematic false resistance results). To date, such epistatic interactions have only been reported for streptomycin that is now rarely used. By analyzing more than 31,000 MTBC genomes, we demonstrated that eis C-14T promoter mutation, which is interrogated by several genotypic DST assays endorsed by the World Health Organization, cannot confer resistance to amikacin and kanamycin if it coincides with loss-of-function (LoF) mutations in the coding region of eis. To our knowledge, this represents the first definitive example of antibiotic reversion in MTBC. Moreover, we raise the possibility that mmpR (Rv0678) mutations are not valid markers of resistance to bedaquiline and clofazimine if these coincide with LoF mutation in the efflux pump encoded by mmpS5 (Rv0677c) and mmpL5 (Rv0676c).

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“…Many of the isolates with discordant pDST results had an MIC that was a single dilution above the breakpoint. It should also be noted that Rv0678 mutations have variable MICs, making a clear assessment of resistance determination challenging (11,26). Testing on an alternative phenotypic method, however, does seem to be a reasonable approach to confirm resistance at this stage when discordance is detected.…”

Section: Discussionmentioning

confidence: 99%

A Multimethod, Multicountry Evaluation of Breakpoints for Bedaquiline Resistance Determination

Ismail

Ando

Borroni

et al. 2020

Antimicrob Agents Chemother

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Criteria defining bedaquiline resistance for tuberculosis have been proposed addressing an emerging concern. We evaluated bedaquiline phenotypic drug susceptibility testing (pDST) criteria using drug-resistant tuberculosis clinical isolates tested at five reference laboratories. Isolates were tested at the proposed bedaquiline MGIT960 and 7H11 Agar Proportion (AP) critical concentrations, and dilutions higher. The epidemiological cut-off value for the broth microdilution (BMD) plates (frozen and dry) was investigated. Any isolate testing resistant had Sanger sequencing performed (atpE and Rv0678 genes). The composite reference standard (CRS) defined susceptibility or resistance as is, if all pDST methods agreed. If pDST was discordant sequencing results was used for final classification. Geographically-diverse and bedaquiline unexposed isolates were tested (N=495). The epidemiological cutoff value for BMD was confirmed to be 0.12 μg/mL. The majority of isolates were susceptible by all methods (467/495; 94.3%) and 28 were resistant by at least one method; of which 4 were resistant by all methods. 12/28 harboured Rv0678 mutations exclusively. Isolates with insertions/deletions were more likely to be resistant by more than one method (5/7) compared with isolates having a single nucleotide polymorphism (1/5). Applying the CRS to 24 discordant pDST, BMD dry correctly detected most (15/24; 63%), followed by MGIT960 and BMD frozen (13/24; 61%) and lastly AP (12/24; 50%). Applying the CRS, the prevalence of bedaquiline resistance was 2.2% and ranged from 1.4% to 3.4%, dependent on the method used. All methods performed well for bedaquiline susceptibility determination, however resistance detected should be investigated by a second alternative method.

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Reduced susceptibility and resistance to bedaquiline in clinical M. tuberculosis isolates

Cited by 39 publications

References 45 publications

Comparative efficacy of the novel diarylquinoline TBAJ-587 and bedaquiline against a resistantRv0678mutant in a mouse model of tuberculosis

Comparative efficacy of the novel diarylquinoline TBAJ-587 and bedaquiline against a resistantRv0678mutant in a mouse model of tuberculosis

The role of epistasis in amikacin, kanamycin, bedaquiline, and clofazimine resistance inMycobacterium tuberculosiscomplex

A Multimethod, Multicountry Evaluation of Breakpoints for Bedaquiline Resistance Determination

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