MabADAPT · Fundamental biological adaptations underlying persister formation and multi-stress tolerance in Mycobacterium abscessus and their impact on host-pathogen interactions

The rapid spread of bacterial antimicrobial resistance (AMR) poses a major global health threat, leading to treatment failures. Beyond resistance, bacteria employ also other strategies to counteract antibiotics. Persisters represent a bacterial subpopulation that can survive transient exposure to different stresses, such as nutrient depletion, low pH or the presence of antibiotics. Increasing evidence suggests clinical importance of persister formation, since their ability to regrow after termination of antibiotic treatment is a cause for prolonged and relapsing course of many bacterial infections. Formation of persisters also accelerates the emergence of antibiotic resistance, worsening the problem of bacterial AMR. Recent research indicates that mechanisms involved in persister formation may also enhance the overall adaptability of bacteria to antibiotics and stresses imposed by host immune system. Targeting these dual mechanisms could represent a unique two-pronged strategy to improve treatment efficiency, preventing resistance development and decreasing bacterial survival within the host. However, our understanding of these mechanisms is very limited. Combining microbiology, molecular biology and infection models, together with cutting-edge techniques such as metabolomics and transcriptomics, I propose to identify key biological adaptations underlying the formation of bacterial persisters and to explore their impact on host-pathogen interactions and infection outcomes. As an emerging pathogen known for its high antibiotic resistance and ability to endure harsh conditions during infection, I selected Mycobacterium abscessus (Mabs) as a clinically relevant model for this study. Discovery of such adaptations can lead to the development of innovative treatments tackling not only Mabs infections, but also the broader challenge of AMR.