Development of host-directed therapy for targeting Mycobacterium tuberculosis persisters

Antimicrobial resistance (AMR) is a significant global challenge. It is estimated that nearly 10 million people will die from infection with multi-drug resistant bacteria by 2050 if novel antimicrobials and advanced control measures are not introduced. While mechanisms of acquired AMR are well established the biology of persisters, drug-sensitive bacteria that survive exposure to bactericidal drugs and result in treatment failure, remains poorly characterised. Persisters are particularly important in tuberculosis (TB) which is the main cause of mortality from infection in Southeast Asia. Indonesia has the world’s second highest TB burden which is further complicated by the low rate of treatment coverage, low successful treatment rate of multi-drug resistant (MDR)TB and high number of TB re-treatment cases. The TB relapse rate in Indonesia is nearly 4 times higher than TB reoccurrences in Leicester, indicating that a higher proportion of patients are not cured or do not adhere to prescribed regimens. This challenging situation has a negative impact on Indonesian health system, people well-being and economy. Thus, reducing TB recurrence by improving TB treatment and educating patients is the key need in Indonesia. TB requires prolonged chemotherapy with a combination of drugs. Mycobacterium tuberculosis (Mtb), the causative TB agent survives in infected patients by adopting a special difficult-to-culture (DC) persister-like state. These drug recalcitrant DC Mtb persisters are believed to cause TB relapse and failed TB treatment. DC Mtb are highly abundant TB patients and can be recovered from sputum. Host immune factors associated with the inflammatory response trigger formation of DC Mtb, while anti-inflammatory drug dimethyl fumarate (DMF) removes DC Mtb from infected animal tissue. The central hypothesis of this proposal is that DC Mtb can be eliminated via host-directed therapy by altering the immune response and the niche that promotes their formation and survival. This collaborative project between the University of Leicester (UoL) and Hasanuddin University (UNHAS) is aimed to investigate the biology of DC Mtb persisters and to develop new chemotherapeutic for rapid eradication of DC Mtb in patients. This will be achieved by completing the following objectives: (1) discovery of drugs with dual anti-mycobacterial and anti-inflammatory activities suitable for elimination of DC Mtb; (2) determination of the factors that affect abundance of DC Mtb in infected patients; (3) exploration of the molecular mechanisms underpinning bactericidal effects of the new drugs on Mtb persisters; (4) to increase public awareness about the importance of adhering to treatment and eliminating Mtb persisters. The proposal applicants will embrace a collaborative multidisciplinary approach supported by complementary expertise in clinical TB research, generation and assessment of Mtb persisters, infection studies, omics technologies. Research activities will be enhanced by interactions with key stakeholders, clinicians, researchers, patients. These interactions will be directed on identification of further health and research needs concerning TB treatment and management, formulation of innovative solutions and increase of public awareness about the importance of AMR, TB and Mtb persisters. The proposed project will strengthen research in both institutions by enabling exchange of materials, protocols, and knowledge, provision of training, publishing of research finding and exploring translational opportunities. The development of host directed anti-persister therapy will have a direct impact on improvement of TB treatment and management in Indonesia and will stimulate expansion of the existing collaboration for controlling major infectious diseases.