Remembering the Host in Tuberculosis Drug Development

Abstract

New therapeutics to augment current approaches and shorten treatment duration are of critical importance for combating tuberculosis (TB), especially those with novel mechanisms of action to counter the emergence of drug-resistant TB. Host-directed therapy (HDT) offers a novel strategy with mechanisms that include activating immune defense mechanisms or ameliorating tissue damage. These and related concepts will be discussed along with issues that emerged from the workshop organized by the Stop TB Working Group on New Drugs, held at the Gordon Research Conference for Tuberculosis Drug Development in Lucca, Italy in June 2017, titled "Strategic Discussion on Repurposing Drugs & Host Directed Therapies for TB." In this review, we will highlight recent data regarding drugs, pathways, and concepts that are important for successful development of HDTs for TB.

Keywords: drug development; host-directed therapy; macrophage; meningitis; tuberculosis.

Figure 1.

Possible effects of host-directed therapies (HDTs) on the outcome of tuberculosis (TB) treatment. Improved TB treatment outcomes with HDTs are reliant either on the ability of these agents to accelerate bacterial clearance or reduce the lung damage associated with granulomatous disease. Some agents promise to modulate both these effects to improve treatment outcomes. The use of appropriate outcome measures is critical for ensuring that the best potential HDTs are advanced in clinical trials. In this regard, recent developments such as monitoring changes in pathology, using novel tracers, and assessing the presence of differentially culturable bacteria (DCTB), which resist treatment, may prove important for prioritizing agents for further human studies. HAP, hypoxia-activated prodrug; IL, interleukin; PET-CT, positron emission tomography-computed tomography; TNF, tumor necrosis factor.