Development of an in vitro model for Non-Replicating Persistent Mycobacterium tuberculosis, and an investigation of the novel phenotype

Tuberculosis is the primary cause of global death by a single infectious agent. This widespread infection is assisted by the existence of a large reservoir of disease in the form of Latent Tuberculosis which is thought to infect over ¼ of the world's population. Latent Tuberculosis is caused when an existing Mycobacterium tuberculosis infection is encapsulated within a granuloma and the bacilli adapt their physiology to cope with this hostile environment known as the Non-Replicating Persistent (NRP) state. The background of Tuberculosis, Latent Tuberculosis and scientific modelling of these states is discussed in Chapter 1. The first results chapter of this thesis, Chapter 2, sets out a novel multi-stress in vitro model of Latent Tuberculosis to create a more physiologically relevant M. tuberculosis NRP phenotype. Chapter 3 uses the in vitro model proposed in Chapter 2, along with a control in vitro model to conduct widespread antimicrobial testing against a variety of antimicrobials; from frontline, second line and antibiotics in clinical trials to novel compound libraries. This uncovered an exceptionally antibiotic tolerant phenotype, not previously seen in less physiologically relevant models of Latent ... (continues)