Periodic Reporting for period 4 - RespiriNTM (Progress novel assets (one FIH start) for non-tubercular mycobacteria that may act synergistically with bedaquiline)
Reporting period: 2023-11-01 to 2025-04-30
Mycobacterium avium (Mav) and Mycobacterium abscessus (Mab) cause millions of infections worldwide each year. Unlike the well-known, related species Mycobacterium tuberculosis, there are currently no effective antibiotics against these pathogens and mortality rates can be as high as 30%. Therefore, there is an urgent need for antibiotics that can treat the debilitating diseases that are caused by the Non-Tuberculous Mycobacteria (NTM) M. avium and M. abscessus. The RespiriNTM project consists of three pillars of work, the first pillar aimed to develop novel antibiotics that target the NTM respiratory pathway, the energy centre of the bacteria. Potential treatment options culminating from this will be combined with the recently developed antibiotic bedaquiline that also targets the respiratory pathway, thus creating a double blow to the bacterium. In the second pillar, RespiriNTM will also cast a wider net in its search for novel antibiotics, by targeting human factors that are needed for NTM to survive in the infected host. The third pillar is focused on rifamycins. BioVersys has identified a novel orally bioavailable rifamycin that has been engineered to by-pass intrinsic resistance in MAB, while maintaining its potency across a large panel of NTM species. The RespiriNTM consortium will be instrumental in its continued development, both preclinically and clinically. Overall, through this project we aim to develop desperately needed antibiotics that work against M. avium and M. abscessus which are an increasing threat to global health.
The overarching aim of the project is to discover and develop new antibiotics against Non-Tuberculous Mycobaterial (NTM) diseases.
We previously made significant progress towards this goal along several avenues, including the biochemical and structural characterization of cytochrome bc inhibitors, the discovery of a host directed therapeutic active against M. avium and that of novel inhibitors acting on the Mmpl3 protein from M. avium. However, continued development of these new molecules was not viable. Despite the discontinuation of several of the original planned activities, the consortium produced several publications that brought new insight into these poorly studied pathogens, such as the development of new models for NTM infections (doi: 10.3389/fcimb.2022.872361 doi: 10.1016/j.tim.2023.11.011) new insights into the host immune response to NTM (doi: 10.3389/fimmu.2022.1075473) and new approaches for host-directed therapeutics for NTM infections (doi: 10.1111/imr.12951 doi: 10.1128/spectrum.00167-24).
To explore and exploit a more advanced asset into preclinical development, a program under study at BioVersys was incorporated into the project starting from January 2024. Derived from the company’s Ansamycin Chemistry platform, the BioVersys asset entered the project at Lead stage. Therefore, project activities for the development of this asset are geared towards obtaining the necessary dataset to validate it as a preclinical candidate and subsequently progress it into IND-enabling studies.
We previously made significant progress towards this goal along several avenues, including the biochemical and structural characterization of cytochrome bc inhibitors, the discovery of a host directed therapeutic active against M. avium and that of novel inhibitors acting on the Mmpl3 protein from M. avium. However, continued development of these new molecules was not viable. Despite the discontinuation of several of the original planned activities, the consortium produced several publications that brought new insight into these poorly studied pathogens, such as the development of new models for NTM infections (doi: 10.3389/fcimb.2022.872361 doi: 10.1016/j.tim.2023.11.011) new insights into the host immune response to NTM (doi: 10.3389/fimmu.2022.1075473) and new approaches for host-directed therapeutics for NTM infections (doi: 10.1111/imr.12951 doi: 10.1128/spectrum.00167-24).
To explore and exploit a more advanced asset into preclinical development, a program under study at BioVersys was incorporated into the project starting from January 2024. Derived from the company’s Ansamycin Chemistry platform, the BioVersys asset entered the project at Lead stage. Therefore, project activities for the development of this asset are geared towards obtaining the necessary dataset to validate it as a preclinical candidate and subsequently progress it into IND-enabling studies.
This project aims to develop novel antibiotics against two pathogens that represent an increasing threat to global health (Mycobacterium avium and Mycobacterium abscessus) and currently have no suitable treatment options. Mycobacterium avium complex and Mycobacterium abscessus subspecies cause several hundreds of thousands of infections worldwide each year. Unlike the well-known related species M. tuberculosis, there are currently limited and poor treatment options to address these pathogens with significant levels of relapse and unacceptably high mortality rates, approaching 30%. 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 for millions of infected patients. Our work on the Ansamycin Chemistry reveals a development opportunity of a new, highly potent antibiotic against M. avium and M. abscessus that would potentially provide the best-in-class treatment option for these challenging infections.