Treatment of Highly Drug-Resistant Pulmonary Tuberculosis

Conradie, Francesca; Diacon, Andreas H.; Ngubane, Nosipho; Howell, Pauline; Everitt, Daniel E.; Crook, Angela M.; Mendel, Carl M.; Egizi, Erica; Moreira, Joanna; Timm, Juliano; McHugh, Timothy D.; Wills, G; Bateson, Anna; Hunt, Robert D.; Niekerk, Christo van; Li, Mengchun; Olugbosi, Morounfolu; Spigelman, Melvin

doi:10.1056/nejmoa1901814

Cited by 687 publications

(649 citation statements)

References 23 publications

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“…In this context, WHO has recently updated the treatment for MDR-TB, by recommending two possible regimens (the longer regimen and the shorter one), both including BDQ and other drugs (Caminero et al, 2019;World Health Organization [WHO], 2019b). Interestingly, in a recent study, NIX-TB trial, a three-drug regimen including linezolid, BDQ and pretomanid was tested with XDR-and MDR-TB patients; the therapy was successful for 90% of patients (Conradie et al, 2020). As evident, BDQ use is rapidly spreading, and 90 countries reported having imported or started using BDQ by the end of 2018 (World Health Organization [WHO], 2019a).…”

Section: Introductionmentioning

confidence: 99%

In vitro Study of Bedaquiline Resistance in Mycobacterium tuberculosis Multi-Drug Resistant Clinical Isolates

et al. 2020

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Tuberculosis (TB) is one of the major causes of death related to antimicrobial resistance worldwide because of the spread of Mycobacterium tuberculosis multi-and extensively drug resistant (multi-drug resistant (MDR) and extensively drug-resistant (XDR), respectively) clinical isolates. To fight MDR and XDR tuberculosis, three new antitubercular drugs, bedaquiline (BDQ), delamanid, and pretomanid were approved for use in clinical setting. Unfortunately, BDQ quickly acquired two main mechanisms of resistance, consisting in mutations in either atpE gene, encoding the target, or in Rv0678, coding for the repressor of the MmpS5-MmpL5 efflux pump. To better understand the spreading of BDQ resistance in MDR-and XDR-TB, in vitro studies could be a valuable tool. To this aim, in this work an in vitro generation of M. tuberculosis mutants resistant to BDQ was performed starting from two MDR clinical isolates as parental cultures. The two M. tuberculosis MDR clinical isolates were firstly characterized by whole genome sequencing, finding the main mutations responsible for their MDR phenotype. Furthermore, several M. tuberculosis BDQ resistant mutants were isolated by both MDR strains, harboring mutations in both atpE and Rv0678 genes. These BDQ resistant mutants were further characterized by studying their growth rate that could be related to their spreading in clinical settings. Finally, we also constructed a data sheet including the mutations associated with BDQ resistance that could be useful for the early detection of BDQ-resistance in MDR/XDR patients with the purpose of a better management of antibiotic resistance in clinical settings.

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Section: Introductionmentioning

confidence: 99%

In vitro Study of Bedaquiline Resistance in Mycobacterium tuberculosis Multi-Drug Resistant Clinical Isolates

et al. 2020

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“…The World Health Organization subsequently added BDQ to its Model List of Essential Medicines (World Health Organization, 2019b). As of 2019, all seven ongoing phase III clinical trials of combination therapies for drug resistant TB include BDQ as a core component (World Health Organization, 2019a), with one trial reporting favorable outcomes in 90% of patients with extensively-drug resistant TB or complicated forms of multi-drug resistant TB (Conradie et al, 2020). It has been estimated that 80% of people with drug resistant TB would benefit from BDQ (Médecins Sans Frontières, 2019).…”

Section: Introductionmentioning

confidence: 99%

Structure of mycobacterial ATP synthase with the TB drug bedaquiline

Guo

Courbon

Bueler

et al. 2020

Preprint

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SummaryTuberculosis (TB), the leading cause of death by infectious disease worldwide, is increasingly resistant to first line antibiotics. Developed from a screen against Mycobacterium smegmatis, bedaquiline can sterilize even latent M. tuberculosis infections that may otherwise persist for decades and has become a cornerstone of treatment for multidrug resistant and extensively-drug resistant TB. Bedaquiline targets mycobacterial ATP synthase, an essential enzyme in the obligate aerobic Mycobacterium genus. However, how the drug binds the intact enzyme is unknown. We determined the structure of M. smegmatis ATP synthase with and without bedaquiline. The drug-free structure reveals hook-like extensions from the enzyme’s α subunits that inhibit ATP hydrolysis in low-energy conditions, such as during latent infections. Bedaquiline binding induces global conformational changes in ATP synthase, creating tight binding pockets at the interface of subunits a and c. These binding sites explain the drug’s structure-activity relationship and its potency as an antibiotic for TB.

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“…The demonstrated 90% cure rates observed in a single-arm, open-label trial in South Africa has prompted approval by the US Food and Drug Administration (FDA), despite the high frequency of adverse events, including bone marrow suppression and peripheral neuropathy, due to linezolid. These advances show that with wise investments and a well-thought strategy that pursues development of a full regimen composed of new and existing or re-purposed drugs rather than of individual new drugs-as promoted by the WHO Target Regimen Profiles [13] -may be conducive to success despite the obvious challenges that TB research poses. This now needs to be consolidated and accelerated, so that we can hope to obtain a shorter and safer novel regimen that can treat TB irrespective of pre-existing drug resistance (and thus with reduced need for drug-resistance testing).…”

Section: Which New Tools Are Necessary To End the Tuberculosis (Tb) Ementioning

confidence: 99%

TB Elimination Requires Discovery and Development of Transformational Agents

Lienhardt

Raviglione

2020

Applied Sciences

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The World Health Organization (WHO) End Tuberculosis (TB) Strategy has set ambitious targets to reduce 2015 TB incidence and deaths by 80% and 90%, respectively, by the year 2030. Given the current rate of TB incidence decline (about 2% per year annually), reaching these targets will require new transformational tools and innovative ways to deliver them. In addition to improved tests for early and rapid detection of TB and universal drug-susceptibility testing, as well as novel vaccines for improved prevention, better, safer, shorter and more efficacious treatments for all forms of TB are needed. Only a handful of new drugs are currently in phase II or III clinical trials, and a few combination regimens are being tested, mainly for drug-resistant TB. In this article, capitalising on an increasingly rich medicine pipeline and taking advantage of new methodological designs with great potential, the main areas where progress is needed for a transformational improvement of treatment of all forms of TB are described.

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Treatment of Highly Drug-Resistant Pulmonary Tuberculosis

Abstract: which is the author's version after external peer review and before publication in the Journal, is available under a CC BY license at PMC6955640.

Cited by 687 publications

References 23 publications

In vitro Study of Bedaquiline Resistance in Mycobacterium tuberculosis Multi-Drug Resistant Clinical Isolates

In vitro Study of Bedaquiline Resistance in Mycobacterium tuberculosis Multi-Drug Resistant Clinical Isolates

Structure of mycobacterial ATP synthase with the TB drug bedaquiline

TB Elimination Requires Discovery and Development of Transformational Agents

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