Tricyclic-Spirolactams for the treatment of non-tuberculous mycobacteria Infections – TriSLa-4-NTM

Infections caused by Non-Tuberculous Mycobacteria (NTM) are on the rise worldwide, not only in cystic fibrosis and immuno-compromised patients, but also in immune-competent individuals. These infections represent a major healthcare challenge with treatment using current antibiotics remaining less than optimal and associated with high therapeutic failure. The primary NTMs involved in human pulmonary diseases are Mycobacterium avium Complex (MAC) and Mycobacterium abscessus (MABS) complex, notorious for their inherent resistance to most antibiotic classes. With the added complexity of increasing acquired antibiotic resistance, it is evident that novel drugs are urgently needed.

Proteins of the electron transport chain (ETC) have in recent years emerged as attractive new targets for the development of novel efficacious antibiotics against mycobacteria, though genetic differences between mycobacterial species mean that not all ETC targeting inhibitors are active on MAC and MABS. Recently, members of the current consortium have discovered and worked extensively on the development of a novel class of anti-tuberculosis molecules, named the Tricyclic-Spirolactams (TriSLa), that are potent inhibitors of type II-NADH dehydrogenases (Ndh-2) of the ETC of mycobacteria. During this extensive early drug development research, medicinal chemistry efforts have generated more than 250 TriSLa analogues, and in vitro profiling found that these novel inhibitors maintain strong activity on both MAC and MABS, making them an attractive alternative tool for targeting the NTM ETC. This offers the potential to develop a novel candidate to be included in a poly-therapy treatment for these extremely difficult-to-manage mycobacteria. Based on the extensive knowledge that the consortium has already accumulated regarding the favourable and largely optimised physicochemical and pharmacokinetic properties of the more potent TriSLas, TriSLa-4-NTM proposes to accelerate the development of an efficacious TriSLa-based preclinical candidate for the treatment of pulmonary infections by M. abscessus and M. avium.

To achieve the goal of the TriSLa-4-NTM, the consortium of 4 partners sharing complementary expertise in drug discovery & development, medicinal chemistry, pharmacology, mycobacteriology, NTM genetics and animal models, has structured its R&D pipeline around 3 inter-connected work packages. Firstly, the mechanism of action and in vitro profile of TriSLa on MAC and MABS will be evaluated; this includes the understanding of the importance of media composition on TriSLa activity, and how TriSLa acts in combination with other antibiotics. Secondly, the in vitro and in vivo essentiality and vulnerability of Ndh-2 in MAC and MABS will be assessed using functional genomics. Of interest is that MAC have two Ndh-2 homologues while MABS only have one. This section will also investigate if any genes in MABS impact the efficacy of TriSLa. Thirdly, a large focus of the program will be on the synthesis and pharmacokinetic/ADME profiling of lead TriSLa inhibitors for selection of optimised candidates for in vivo efficacy studies, their efficacy evaluation on MAC/MABS infected zebrafish, and critically, the evaluation of TriSLa efficacy on murine models of pulmonary MABS/MAC infection, determination of their minimal effective dose, and finally, their efficacy in combination with other antibiotics.

The goal of TriSLa-4-NTM research program will be to deliver a well-characterised and optimised set of TriSLa inhibitors efficacious against murine models of NTM infection, ready to complete pre-clinical studies, with the ultimate goal of developing a clinical candidate for the treatment of pulmonary NTM infections. In addition, this research will strengthen the expertise in France in animal models for NTM infections, an expertise that is essential for antibiotic drug development for NTMs.