Functional Ethionamide boosters: a novel combination for tuberculosis therapy The scope of this action is to generate a small molecule clinical candidate that can boost the activity of ethionamide and revert the existing resistance to this drug, by acting on bacterial transcriptional regulators. The associated, dose dependant side effects for ethionamide observed at the currently required human doses together with the high pre-existing levels of resistance in patients has limited the use of ethionamide as a TB front-line agent. However, ethionamide is considered an essential drug for MDR-TB treatment even today and could well be positioned back into first line, replacing Isoniazid as the ‘fast killing’ agent acting on mycolic acid synthesis, once the bio-activation of ethionamide is optimal. This action aims at identifying novel small molecules that are capable of: a) increasing the level of bioactivation of ethionamide, therefore reducing the levels of ETH required to achieve maximal efficacy both in vitro (>10-fold) and in vivo (>3-fold); b) revert pre-existing ETH clinical resistance using a very low oral dose. This will make it possible to open up the scope of the ETH field of use to both drug sensitive and multi-drug-resistant (MDR) patients. This action intends to progress these new compounds from the candidate selection stage to a proof of concept as ethionamide booster in TB patients. The Portfolio Building Network (PBN), Pillar C of the IMI2 JU AMR Accelerator programme, will address the limited pipeline of treatments and preventions for AMR infections by enabling vibrant and nimble collaborations between EFPIA companies and small and medium-sized enterprises (SMEs) and/or academics that will advance the R&D pipeline of new and innovative agents to address AMR. The expected impact of actions selected under this Call will be to: (1) contribute to the development of a vibrant AMR research environment in the EU and strengthen the competitiveness and industrial leadership of Europe; (2) contribute to the EU’s ambition of being a ‘best practice region’ for addressing AMR; (3) enhance the overall pipeline of medicines for patients with AMR infections and advance new and innovative agents.