Tuberculosis (TB) is the world’s leading infectious disease. It killed 1.7 million people in 2016 and 10.4 million people developed active TB in the same year. In 2016, 480’000 of TB cases were multidrug-resistant (MDR-TB) and 9% percent of those cases are extensively drug-resistant (XDR), with mortality rates as high as 70%. Ethionamide (ETH) is a vital part of the WHO essential medicines list of 2nd-line TB therapy for MDR-TB, however, ETH suffers from significant levels of resistance and side effects at current dosing levels. BVL-GSK038 and BVL-GSK098 are proprietary to BioVersys/GlaxoSmithKline and have been developed through an extensive Lead Optimization program with collaborators from Lille University. Low doses of both compounds fully restore and “boost” the activity of ETH to rapidly kill Mycobacterium tuberculosis (Mtb) including MDR strains at significantly lower doses of ETH than previously reported, thus making MDR-TB sensitive to ETH once again. Through a comprehensive IND enabling package including in vitro and in vivo assessment of ETH with BVL-GSK038 and BVL-GSK098, including PK/PD, resistance development, safety, mechanism of action and synergistic studies with different drug compound combinations and then first in human clinical studies the consortium aims to: i) Define the future placement of a boosted ETH (ETH + BVL-GSK038 or BVL-GSK098) in a universal TB treatment regimen, including overcoming MDR-TB with improved safety, time to cure and relapse rates; Ultimately, we expect to identify a new and clinically proven TB regimen that leads to better patient outcomes independently of the starting resistance status of the TB infection. The TB and wider scientific communities will benefit from an improved understanding of ETH and the exploration of a novel class of therapeutic compounds acting on transcriptional modulators (BVL-GSK038 and BVL-GSK098).

Non-tuberculous mycobacteria, such as Mycobacterium avium complex (MAC) and Mycobacterium abscessus, cause lung diseases resembling TB, mainly in immune-compromised patients or patients suffering from other lung diseases (e.g. cystic fibrosis). The incidence and prevalence of lung diseases caused by NTM are increasing worldwide. Importantly, in the US and Japan, as well as in other areas of the world where TB has declined, NTM disease is already at least three times more prevalent than TB. Treatment of NTM diseases relies on antibiotic combinations, however the drugs active against NTM are rather few and mainly different than those active against TB. These NTM treatments for the most common species (MAC and M. abscessus) are much less active than the current anti-TB regimen is for TB treatment. It is often necessary to administer antibiotic combinations for at least 12-24 months. The long and complex drug regimen that is currently recommended as a treatment against NTM-caused diseases carries the risk of inducing resistance in NTM. Several studies have already shown the existence and emergence of multidrug resistant NTM. The overall objective of RESPIRI-NTM is to find new drug candidates as potential components of a new, more efficient combination drug regimen against NTM that is less prone to resistance and allows shortening of treatment duration for NTM and multidrug-resistant NTM. Such a drug combination will synergistically target the energy metabolism of NTM or complementary targets. To achieve this, we will advance recently discovered inhibitors of the mycobacterial respiratory pathway. In addition, we will perform a novel, phenotypic screen in order to identify novel targets in NTM. We will also target host-factors that are essential for the intracellular survival of NTM. Finally, we have a potential rifamycin candidate to progress into FIH. Together, we present a comprehensive plan to find novel strategies to combat non-tuberculous mycobacteria, shorten treatment time and reduce chances of drug resistance.

Train2Target is a multidisciplinary European Training Network built to address the challenge of the discovery of alternative antimicrobials. Innovative strategies to deliver a next generation of drugs are urgently needed. The alarming threats and spread of multi-drug resistant bacteria is currently leaving clinicians with very limited options to combat infections especially those from Gram-negative pathogens. The Train 2Target research programme focuses on the assembly of the well-known bacterial cell envelope from a new perspective. Indeed it aims to inhibit novel targets in envelope biogenesis by altering the function and misbalancing the coordination of envelope assembly machines, which build and assemble the Gram-negative bacterial envelope. A wide variety of chemical classes and compounds sources will be screened using innovative biochemical, biophysical and genetic assays to identify valuable hit scaffolds to be optimized into druggable leads. The high quality and credibility of our consortium is ensured by a strong interdisciplinary academia-industry partnership to encompass different complementary expertise ranging from microbiology, bacterial genetics, biochemistry, cell imaging, structural biology, biophysics and chemical synthesis. Our 9 academic groups are all renowned leaders in the cell envelope biogenesis field, whereas the complementary 5 SMEs and 3 Industry partners are specialised in drug discovery and development of novel anti-infective drugs. This unique combination of scientific excellence and industrial know-how in drug discovery covers the entire process from the design to the implementation of innovative antibacterial strategies and lead identification. Train2Target also represents a unique research platform to train 15 Early Stage Researchers and equip them with the necessary scientific and transferable skills that will make them highly competitive for both top European research institutions and the pharma/biotech job market.