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.

Disseminated Mycobacterium bovis Infection Complicated by Meningitis and Stroke: A Case Report

“…Despite the availability of effective antimicrobial agents, patients with TB meningitis remain at risk for paradoxical worsening on therapy (labeled immune reconstitution inflammatory syndrome [IRIS] in HIV+ patients) [ 36 ] and severe complications such as vasculitis leading to ischemic stroke, which may be driven by a pathologic immune response [ 37 ]. Consequently, there has been considerable interest in the use of adjunctive host-directed therapies in tuberculosis [ 38 ]. Corticosteroids have been shown to improve mortality [ 13 ], whereas aspirin may reduce the risk of stroke [ 14 , 15 ].…”

Mycobacterium tuberculosis Shikimate Pathway Enzymes as Targets for the Rational Design of Anti-Tuberculosis Drugs

“…Host-directed therapies have emerged as a novel and promising approach to treat TB, whose modulation of host response is likely to avoid the development of bacterial resistance [165,166]. Unlike conventional antibiotics aimed at targeting the bacteria, host-directed therapy aims at targeting the host immune response either by directly boosting its ability to effectively eliminate the bacterial load or reduce the lung damage associated with granulomatous disease.…”

Small Animal Models for Human Immunodeficiency Virus (HIV), Hepatitis B, and Tuberculosis: Proceedings of an NIAID Workshop

“…He concluded that there are major differences in the quality of T-cell polarization between mice and primates, leading to major differences in function and migration. P. Karakousis showed interest in host-directed therapies (HDT) for TB since Mtb is known to subvert host responses and induce lung damage [39,40]. Preclinical endpoints of HDT include the assessment of bacterial clearance in the host and histological or radiographic assessment of lung inflammation.…”