Progress new assets (one pre-new molecular entity and one first-time-in-human start) for tuberculosis that act synergistically with bedaquiline, cytochrome bc or cytochrome bd inhibitors

Project Information

RespiriTB

Grant agreement ID: 853903

DOI

10.3030/853903

EC signature date 8 May 2019

Start date 1 May 2019

End date 31 October 2026

Funded under

• SOCIETAL CHALLENGES - Health, demographic change and well-being

Total cost

€ 10 062 900,01

EU contribution

€ 6 840 000,00

Coordinated by

ACADEMISCH ZIEKENHUIS LEIDEN
Netherlands

Periodic Reporting for period 5 - RespiriTB (Progress new assets (one pre-new molecular entity and one first-time-in-human start) for tuberculosis that act synergistically with bedaquiline, cytochrome bc or cytochrome bd inhibitors)

Reporting period: 2023-11-01 to 2025-04-30

Summary of the context and overall objectives of the project

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains the leading infectious cause of death worldwide, claiming more than 1.5 million lives each year. Treatment requires long, complex regimens and is increasingly challenged by the rise of drug resistance. Multidrug-resistant TB (MDR-TB) in particular represents a growing global health threat, highlighting the urgent need for shorter, safer, and more effective therapies.

New treatments will reduce the duration and complexity of TB therapy, improve adherence, and curb resistance development. This will benefit patients, healthcare systems, and society as a whole, particularly in regions most affected by MDR-TB.

RespiriTB aims to deliver new therapeutic options for TB by:
̶ Developing inhibitors of the mycobacterial respiratory chain (cytochrome bc1 and bd).
̶ Advancing at least one novel candidate to first-in-human (FIH) trials.
̶ Exploring additional drug targets such as mycothione reductase.
̶ Investigating host-directed therapies (HDTs) to support bacterial clearance.
̶ Introducing innovative drug delivery approaches such as long-acting injectable formulations.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

1. Cytochrome inhibitors ̶ The consortium advanced the back-up compound Respiri-1241 as the lead cytochrome bc1 inhibitor due to its favorable potency and safety profile. Respiri-1241 has been nominated as a GLP-toxicology candidate and handed over to the Gates Medical Research Institute for progression within the ERA4TB consortium. Cryo-EM structures confirmed its binding mode, supporting regulatory submissions. In parallel, a dual bc1/bd inhibitor (CK-2-63) was identified that overcomes known resistance mutations, offering a new route for next-generation inhibitors.

2. Mycothione reductase ̶ Structural biology efforts delivered crystal structures of Mtr in complex with inhibitors, but no consistent link with anti-TB activity could be established. The program was therefore deprioritized as a development track, though the findings contribute important scientific knowledge.

3. Host-directed therapies ̶ Several candidate HDTs were tested in human primary cell models and in combination with standard regimens. Some showed activity, but effective concentrations were incompatible with safe in vivo use. These candidates were not progressed further, but the translational assays developed remain a valuable resource for future TB research.

4. Long-acting injectable bedaquiline ̶ A major milestone was achieved with the start of the first-in-human clinical trial of intramuscular long-acting bedaquiline. Thirty-two healthy volunteers were enrolled across three dose groups. In parallel, a novel mouse model demonstrated that single-dose administration can protect against TB infection at safe exposure levels, further strengthening the potential of bedaquiline long acting injectable for TB preventive treatment.

5. Novel scaffolds ̶ A new series of compounds targeting MenG, an enzyme in menaquinone biosynthesis, was discovered. The series shows in vivo activity against Mtb and the ability to counteract resistance to bedaquiline. It is now advancing towards pre-NME criteria with discussions ongoing for external partnership.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

RespiriTB has made substantial progress towards expanding the TB drug pipeline. The advancement of Respiri-1241 to pre-clinical development ensures continuity beyond the project. The discovery of a dual bc1/bd inhibitor introduces a new mechanism less vulnerable to resistance. The first-in-human trial of long-acting injectable bedaquiline represents a transformative step towards simplified, adherence-independent regimens for both treatment and prevention.

Although the Mtr and HDT programs did not yield drug candidates, they generated structural knowledge and translational tools that will benefit the broader research community. The MenG inhibitor series adds a novel mechanism of action and may provide a way to reverse bedaquiline resistance, addressing a critical emerging challenge.

Together, these achievements are expected to shorten treatment, improve adherence, and reduce resistance, thereby contributing to global TB control and the fight against antimicrobial resistance.

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