Natural Polymorphisms in Mycobacterium tuberculosis Conferring Resistance to Delamanid in Drug-Naive Patients

Reichmuth, Martina L.; Hömke, Rico; Zürcher, Kathrin; Sander, Peter; Avihingsanon, Anchalee; Collantes, Jimena; Loiseau, Chloé; Borrell, Sònia; Reinhard, Miriam; Wilkinson, Robert J.; Yotebieng, Marcel; Fenner, Lukas; Böttger, Erik C.; Gagneux, Sébastien; Egger, Matthias; Keller, Peter M.

doi:10.1128/aac.00513-20

Cited by 13 publications

(8 citation statements)

References 35 publications

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“…These included 192_193insG, 193_193del (I67fs) and M146T mutations in mmpR5 and L49P in ddn , with all four variants found in > 20 isolates. Although some studies have observed a correlation between the length of BDQ treatment and the acquisition of mutations in atpE or mmpR5 43 , the pre-existence of such mutations in BDQ/DLM/PTM naïve isolates has also been described 8 , 16 , 22 , 38 , 39 , 44 . The use of CFZ, which is known to cause cross-resistance through mutations in mmpR5 8 , has been proposed as a potential explanation.…”

Section: Discussionmentioning

confidence: 99%

“…However, alteration of specific residues in ddn , such as L49P, found in 21 isolates in this study, seemed to confer cross-resistance to both drugs 24 . Nevertheless, as the introduction of PTM in TB treatment regimens is very recent, its use does not provide an explanation for the acquisition of DLM resistance mutations in pre-2014 isolates, but there is evidence of pre-exposure resistance and naturally occurring polymorphisms 44 .…”

Section: Discussionmentioning

confidence: 99%

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Genetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid

Gomez-Gonzalez

Perdigão

Gomes

et al. 2021

Sci Rep

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Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the deadliest infectious diseases worldwide. Multidrug and extensively drug-resistant strains are making disease control difficult, and exhausting treatment options. New anti-TB drugs bedaquiline (BDQ), delamanid (DLM) and pretomanid (PTM) have been approved for the treatment of multi-drug resistant TB, but there is increasing resistance to them. Nine genetic loci strongly linked to resistance have been identified (mmpR5, atpE, and pepQ for BDQ; ddn, fgd1, fbiA, fbiB, fbiC, and fbiD for DLM/PTM). Here we investigated the genetic diversity of these loci across >33,000 M. tuberculosis isolates. In addition, epistatic mutations in mmpL5-mmpS5 as well as variants in ndh, implicated for DLM/PTM resistance in M. smegmatis, were explored. Our analysis revealed 1,227 variants across the nine genes, with the majority (78%) present in isolates collected prior to the roll-out of BDQ and DLM/PTM. We identified phylogenetically-related mutations, which are unlikely to be resistance associated, but also high-impact variants such as frameshifts (e.g. in mmpR5, ddn) with likely functional effects, as well as non-synonymous mutations predominantly in MDR-/XDR-TB strains with predicted protein destabilising effects. Overall, our work provides a comprehensive mutational catalogue for BDQ and DLM/PTM associated genes, which will assist with establishing associations with phenotypic resistance; thereby, improving the understanding of the causative mechanisms of resistance for these drugs, leading to better treatment outcomes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid

Gomez-Gonzalez

Perdigão

Gomes

et al. 2021

Sci Rep

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“…Importantly, we only consider chromosomal mutations that are not horizontally transferred. However, while plasmid-mediated resistance is a big concern, chromosomal resistance mutations also contribute to resistance in many important pathogens ( 22 , 23 ).…”

Section: Discussionmentioning

confidence: 99%

Comparing treatment strategies to reduce antibiotic resistance in an in vitro epidemiological setting

Angst

Tepekule

Sun

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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The rapid rise of antibiotic resistance, combined with the increasing cost and difficulties to develop new antibiotics, calls for treatment strategies that enable more sustainable antibiotic use. The development of such strategies, however, is impeded by the lack of suitable experimental approaches that allow testing their effects under realistic epidemiological conditions. Here, we present an approach to compare the effect of alternative multidrug treatment strategies in vitro using a robotic liquid-handling platform. We use this framework to study resistance evolution and spread implementing epidemiological population dynamics for treatment, transmission, and patient admission and discharge, as may be observed in hospitals. We perform massively parallel experimental evolution over up to 40 d and complement this with a computational model to infer the underlying population-dynamical parameters. We find that in our study, combination therapy outperforms monotherapies, as well as cycling and mixing, in minimizing resistance evolution and maximizing uninfecteds, as long as there is no influx of double resistance into the focal treated community.

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“… Nimmo et al (2020a) reported the emergence of fbiC A487 frameshift and S534STOP mutations at low frequencies in DR-TB patients following 6 months of treatment. Reichmuth et al (2020) reported the A416V and Y678G fbiC mutations with associated low-level DLM resistance and other fbiC mutations: c1161t, c1680t, g-11a, a-32g, D375N, I128V, K571E, and A505T. The fbiC R322L and N336K mutations detected in PRT-resistant laboratory-generated mutants, contributed to more than half the PRT resistance in vitro .…”

Section: Introductionmentioning

confidence: 96%

“…Similarly DLM resistance was less common in mutants compared to PRT resistance ( Lee et al, 2020a ; Rifat et al, 2020 ). Reichmuth et al (2020) recently investigated several DLM resistance mutations from global clinical isolates naïve to nitroimidazoles. MIC’s of DLM resistant isolates ranged from 0.015 −>8 mg/L in broth micro dilution (BMD).…”

Section: Introductionmentioning

confidence: 99%

Application of Next Generation Sequencing for Diagnosis and Clinical Management of Drug-Resistant Tuberculosis: Updates on Recent Developments in the Field

et al. 2022

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The World Health Organization’s End TB Strategy prioritizes universal access to an early diagnosis and comprehensive drug susceptibility testing (DST) for all individuals with tuberculosis (TB) as a key component of integrated, patient-centered TB care. Next generation whole genome sequencing (WGS) and its associated technology has demonstrated exceptional potential for reliable and comprehensive resistance prediction for Mycobacterium tuberculosis isolates, allowing for accurate clinical decisions. This review presents a descriptive analysis of research describing the potential of WGS to accelerate delivery of individualized care, recent advances in sputum-based WGS technology and the role of targeted sequencing for resistance detection. We provide an update on recent research describing the mechanisms of resistance to new and repurposed drugs and the dynamics of mixed infections and its potential implication on TB diagnosis and treatment. Whilst the studies reviewed here have greatly improved our understanding of recent advances in this arena, it highlights significant challenges that remain. The wide-spread introduction of new drugs in the absence of standardized DST has led to rapid emergence of drug resistance. This review highlights apparent gaps in our knowledge of the mechanisms contributing to resistance for these new drugs and challenges that limit the clinical utility of next generation sequencing techniques. It is recommended that a combination of genotypic and phenotypic techniques is warranted to monitor treatment response, curb emerging resistance and further dissemination of drug resistance.

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Natural Polymorphisms in Mycobacterium tuberculosis Conferring Resistance to Delamanid in Drug-Naive Patients

Cited by 13 publications

References 35 publications

Genetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid

Genetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid

Comparing treatment strategies to reduce antibiotic resistance in an in vitro epidemiological setting

Application of Next Generation Sequencing for Diagnosis and Clinical Management of Drug-Resistant Tuberculosis: Updates on Recent Developments in the Field

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