Current Approaches to Tuberculosis Drug Discovery and Development

Since the first streptomycin trials for TB in 1944, anti-TB drug discovery research has been inspired by the hope of developing a cure for this dread disease. Pre-clinical TB research efforts are complex given the varied metabolic states of the bacteria (coinciding with active versus persistent infection), long doubling time of the MTB pathogen, the requirement for BSL-3 facilities, and labor/time-intensive methodologies for evaluating compound efficacy. Anti-TB drug development paradigms are also challenging, given the duration of clinical trials and the complexity of combination regimen evaluation. For these reasons, it is important to use the most current pre-clinical and clinical tools for the efficient selection and advancement of NMEs. This chapter reviews the current discovery and development paradigms of 5 novel anti-TB agents, relating those efforts to current tools and methodologies to enable effective decision making. These agents include the nitroimidazo derivatives (PA-824 and OPC-67683), the diarylquinoline TMC207 (R207910), the diamine SQ109, and a novel oxazolidinone, PNU-100480. These agents highlight the exciting opportunities in the coming decade to positively impact the global TB health problem. New agents can be discovered and developed through efficient and coordinated discovery and development approaches alongside effective partnerships with governments in the developed and developing world.