TB drug development: immunology at the table

Our understanding of the host-pathogen relationship in tuberculosis (TB) can help guide drug discovery in at least two ways. First, the recognition that host immunopathology affects lesional TB drug distribution means that pharmacokinetic evaluation of drug candidates needs to move beyond measurements of drug levels in blood, whole lungs, or alveolar epithelial lining fluid to include measurements in specific types of lesions. Second, by restricting the replication of M. tuberculosis (Mtb) subpopulations in latent TB infection and in active disease, the host immune response puts Mtb into a state associated with phenotypic tolerance to TB drugs selected for their activity against replicating Mtb. This has spurred a major effort to conduct high throughput screens in vitro for compounds that can kill Mtb when it is replicating slowly if at all. Each condition used in vitro to slow Mtb's replication and thereby model the phenotypically drug-tolerant state has advantages and disadvantages. Lead candidates emerging from such in vitro studies face daunting challenges in the design of proof-of-concept studies in animal models. Moreover, some non-replicating subpopulations of Mtb fail to resume replication when plated on agar, although their viability is demonstrable by other means. There is as yet no widely replicated assay in which to screen compounds for their ability to kill this 'viable but non-culturable' subpopulation. Despite these hurdles, drugs that can kill slowly replicating or non-replicating Mtb may offer our best hope for treatment-shortening combination chemotherapy of TB.