Periodic Reporting for period 3 - RespiriNTM (Progress novel assets (one FIH start) for non-tubercular mycobacteria that may act synergistically with bedaquiline and cytochrome bc drugs)
Reporting period: 2022-05-01 to 2023-10-31
Non-tuberculous mycobacteria (NTM), or atypical mycobacteria, inhabit the natural environment and can be found, for example, in soil, dust or water. Pathologically, NTM can cause a variety of diseases, including pulmonary infections in immunocompromised patients and/or susceptible populations each year worldwide, and are therefore considered opportunistic pathogens with global health impact. NTM can be divided into slow-growing and fast-growing groups, with the Mycobacterium avium complex (MAC) and Mycobacterium abscessus (MAB) groups being the most important pathogens causing human infections. NTM pulmonary disease (NTM-PD) is a chronic and progressive lung disease that causes respiratory and non-respiratory symptoms such as cough, shortness of breath and fatigue. Unlike the well-known close relative Mycobacterium tuberculosis, there are currently no effective antibiotics against these two pathogens and mortality rates can be as high as 30%. There is an urgent need to accelerate research and development of innovative drugs to treat the debilitating diseases caused by these pathogens.
The RespiriNTM projects aims to tackle the increasing threat of NTM infection by delivering (1) innovative molecule(s) against NTM, which (2) eventually could be combined with other antibiotics, for instance those approved for treating NTM infections, to combat MAC and/or MAB pulmonary infections. Further, the consortium is also addressing (3) human factors that are needed for NTM to survive in the infected host.
The RespiriNTM projects aims to tackle the increasing threat of NTM infection by delivering (1) innovative molecule(s) against NTM, which (2) eventually could be combined with other antibiotics, for instance those approved for treating NTM infections, to combat MAC and/or MAB pulmonary infections. Further, the consortium is also addressing (3) human factors that are needed for NTM to survive in the infected host.
A high-throughput screen (HTS) for inhibitors against Mycobacterium avium and Mycobacterium abscessus was successfully performed, yielding several novel anti-NTM scaffolds. In addition, the consortium performed an HTS against human factors essential for bacterial survival in the human cell. Successful hits were optimised through medicinal chemistry programmes, while structures of target proteins bound to inhibitors were identified and studied to support mechem optimisation. Several promising lead compounds were identified and profiled against a broad assay panel to evaluate the stability, toxicology, pharmacokinetics and dynamics of these molecules, as well as suitable delivery methods. A lead molecule with excellent in vitro activity against M. avium and an encouraging safety pharmacology profile was identified. Unfortunately, and surprisingly, a molecule-associated side effect was identified during the in vivo experiment to investigate the potency of this molecule to attenuate M. avium infections. Further development and optimisation efforts of this scaffold were therefore discontinued. As a result, and as part of the mitigation plan, the consortium explored novel assets outside the consortium, which ultimately led to a new partnership with BioVersys and the introduction of a novel advanced molecule ready for preclinical testing. The consortium is currently working on a transition at management and WP level to support the BioVersys molecule via an amendment.
This project aims to develop novel therapeutics against two key pathogen representatives of the NTM group that form increasing threat to global health: Mycobacterium avium and Mycobacterium abscessus with currently limited or no suitable treatment options. Throughout the duration of the project, the consortium aims to deliver preclinical molecules (anti-NTM molecules or host factors) to target NTM infections, and to execute with at least one molecule a Phase 1 clinical development. Mode of action studies will provide highly valuable details to complement and to support the drug discovery. Given the high number of infections caused by these two pathogens, the potential impacts of this project are vast, as it will improve the outcome of millions of infected patients world-wide.