Bedaquiline–Pretomanid–Linezolid Regimens for Drug-Resistant Tuberculosis

Conradie, Francesca; Bagdasaryan, Tatevik R.; Borisov, Sergey; Howell, Pauline; Mikiashvili, Lali; Ngubane, Nosipho; Samoilova, Anastasia; Skornykova, Sergey; Tudor, Elena; Variava, Ebrahim; Yаblonskiy, Petr; Everitt, Daniel E.; Wills, G; Sun, Eugene; Olugbosi, Morounfolu; Egizi, Erica; Li, Mengchun; Holsta, Alda; Timm, Juliano; Bateson, Anna; Crook, Angela M.; Fabiane, Stella M.; Hunt, Robert D.; McHugh, Timothy D.; Tweed, Conor; Foraida, Salah; Mendel, Carl M.; Spigelman, Melvin

doi:10.1056/nejmoa2119430

Cited by 284 publications

(241 citation statements)

References 19 publications

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“…In another cohort of 472 patients, of whom 90% received linezolid, 28.4% developed peripheral neuropathy and 5.1% myelosuppression [ 104 ]. However, the results of the ZeNix trial were recently published and highlight that in combination with bedaquiline and pretomanid, a reduced dose of linezolid (compared to the doses used in Nix-TB) of 600 mg daily for 26 weeks provided similarly excellent efficacy outcomes [ 105 ]. Additionally, the reduced dose demonstrated significantly improved safety outcomes, with only 4% developing myelosuppression at this dose and 13% requiring dose modification for any cause.…”

Section: Protein Inhibitionmentioning

confidence: 99%

“…The Nix-TB trial demonstrated the efficacy of the combination of bedaquiline and pretomanid in conjunction with the bactericidal activity of linezolid [ 16 ]. A phase III follow-up study, ZeNix, found that this same combination along with a reduced dose of linezolid at 600 mg for 26 weeks produced the optimal balance of efficacy and safety [ 105 ]. The NExT Study was recently published and compared a 6- to 9-month interventional regimen of bedaquiline, levofloxacin, and linezolid with two other drugs (among ethionamide, high-dose isoniazid, terizidone) to the standardized ≥ 9-month injectable-based regimen for MDR-TB [ 151 ].…”

Section: Impaired Energy Metabolism Including Atp Synthesis Cytochrom...mentioning

confidence: 99%

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The Struggle to End a Millennia-Long Pandemic: Novel Candidate and Repurposed Drugs for the Treatment of Tuberculosis

Edwards

Field

2022

Drugs

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This article provides an encompassing review of the current pipeline of putative and developed treatments for tuberculosis, including multidrug-resistant strains. The review has organized each compound according to its site of activity. To provide context, mention of drugs within current recommended treatment regimens is made, thereafter followed by discussion on recently developed and upcoming molecules at established and novel targets. The review is designed to provide a clinically applicable understanding of the compounds that are deemed most currently relevant, including those already under clinical study and those that have shown promising pre-clinical results. An extensive review of the efficacy and safety data for key contemporary drugs already incorporated into treatment regimens, such as bedaquiline, pretomanid, and linezolid, is provided. The three levels of the bacterial cell wall (mycolic acid, arabinogalactan, and peptidoglycan layers) are highlighted and important compounds designed to target each layer are delineated. Amongst others, the highly optimistic and potent anti-mycobacterial activity of agents such as BTZ-043, PBTZ 169, and OPC-167832 are emphasized. The evolving spectrum of oxazolidinones, such as sutezolid, delpazolid, and TBI-223, all aiming to exceed the efficacy achieved with linezolid yet offer a safer alternative to the potential toxicity, are reviewed. New and exciting prospective agents with novel mechanisms of impact against TB, including 3-aminomethyl benzoxaboroles and telacebec, are underscored. We describe new diaryloquinolines in development, striving to build on the immense success of bedaquiline. Finally, we discuss some of these compounds that have shown encouraging additive or synergistic benefit when used in combination, providing some promise for the future in treating this ancient scourge.

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Section: Protein Inhibitionmentioning

confidence: 99%

Section: Impaired Energy Metabolism Including Atp Synthesis Cytochrom...mentioning

confidence: 99%

The Struggle to End a Millennia-Long Pandemic: Novel Candidate and Repurposed Drugs for the Treatment of Tuberculosis

Edwards

Field

2022

Drugs

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“…Indeed, protein synthesis inhibitors have also shown their value as antibiotics ( Kavčič et al., 2020 ) in TB treatment. For instance, oxazolidinones’ contributions to regimen have proven their treatment shortening activity in mouse TB models ( Zhao et al., 2014 ; Xu et al., 2019 ) as well as in the Nix-TB and ZeNix clinical trial ( Conradie et al., 2020 ; Conradie et al., 2022 ). Drug discovery efforts to date have mostly focused on finding safer oxazolidinones because there is very little pre-existing resistance for this class.…”

Section: Approaches To Address Highly Validated Drugs and Targets Com...mentioning

confidence: 99%

“Upcycling” known molecules and targets for drug-resistant TB

Roubert

Fontaine²,

Upton³

2022

Front. Cell. Infect. Microbiol.

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Despite reinvigorated efforts in Tuberculosis (TB) drug discovery over the past 20 years, relatively few new drugs and candidates have emerged with clear utility against drug resistant TB. Over the same period, significant technological advances and learnings around target value have taken place. This has offered opportunities to re-assess the potential for optimization of previously discovered chemical matter against Mycobacterium tuberculosis (M.tb) and for reconsideration of clinically validated targets encumbered by drug resistance. A re-assessment of discarded compounds and programs from the “golden age of antibiotics” has yielded new scaffolds and targets against TB and uncovered classes, for example beta-lactams, with previously unappreciated utility for TB. Leveraging validated classes and targets has also met with success: booster technologies and efforts to thwart efflux have improved the potential of ethionamide and spectinomycin classes. Multiple programs to rescue high value targets while avoiding cross-resistance are making progress. These attempts to make the most of known classes, drugs and targets complement efforts to discover new chemical matter against novel targets, enhancing the chances of success of discovering effective novel regimens against drug-resistant TB.

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“…The recently developed BPaLM and BPaL drug regimens (BPaLM/BPaL) have demonstrated success rates of approximately 90% among people with multidrug-or rifampicin-resistant tuberculosis (MDR/RR-TB) and pre-extensively drug-resistant tuberculosis (pre-XDR-TB) in clinical research studies [3][4][5]-the drug-resistance profiles that represent the vast majority of the DR-TB burden. These regimens hold promise to improve treatment outcomes and experiences in these groups of historically difficult-to-cure patients, simplify care for patients at multiple levels throughout the cascade of care, and improve the currently low treatment success rates.…”

Section: Introductionmentioning

confidence: 99%