Abstract The emergence and spread of disease caused by drug resistant forms of Mycobacterium tuberculosis (M.tb) represents a significant global threat, creating an urgent need for development of preventive and therapeutic strategies efficient against antibiotic-resistant M.tb. We propose a novel concept for developing drugs that cooperate with low doses of IFNg and selectively increase its beneficial effect on host resistance to infections. Essentiallity of the IFNγ pathway in resistance to a broad range of pathogens, including various mycobacterial species, has been convincingly demonstrated both in experimental mouse models and clinical studies. However, pathogens have evolved diverse mechanisms to suppress it. Therefore, therapeutic interventions aimed at restoration and maintanence of the IFNγ pathway may produce significant and long lasting impact on management of chronic infections. This approach will be especially useful in treatment of those chronic infections where the IFN pathway plays an essential role, but is compromised, either systemically (as in HIV and chronic TB infection) or locally (as within TB lesions). Our work will provide a basis for the development of a novel class of drugs targeting the host, not the pathogen, and therefore effective against antibiotic resistant bacteria. By helping control lung damage, these drugs will reduce the development and spread of drug resistant forms of tuberculosis.

Project Narrative The emergence and spread of drug resistant forms of Mycobacterium tuberculosis (M.tb) represents a significant global threat. Given the dearth of new drugs targeting the pathogen, interventions targeting host cells are urgently needed. We propose to develop a novel class of therapeutic agents to enhance a central pathway of host resistance to a number of intracellular pathogens – macrophage activation with interferon gamma (IFNγ). These studies will provide a basis for the development of a novel class of drugs targeting the host, not the pathogen, and therefore, effective against antibiotic resistant bacteria. These drugs will improve outcomes of tuberculosis therapy by controlling the lung damage and reducing the spread of drug resistant forms of tuberculosis.