Host-Directed Therapeutics for Tuberculosis: Can We Harness the Host?

Abstract

SUMMARY Treatment of tuberculosis (TB) remains challenging, with lengthy treatment durations and complex drug regimens that are toxic and difficult to administer. Similar to the vast majority of antibiotics, drugs for Mycobacterium tuberculosis are directed against microbial targets. Although more effective drugs that target the bacterium may lead to faster cure of patients, it is possible that a biological limit will be reached that can be overcome only by adopting a fundamentally new treatment approach. TB regimens might be improved by including agents that target host pathways. Recent work on host-pathogen interactions, host immunity, and host-directed interventions suggests that supplementing anti-TB therapy with host modulators may lead to shorter treatment times, a reduction in lung damage caused by the disease, and a lower risk of relapse or reinfection. We undertook this review to identify molecular pathways of the host that may be amenable to modulation by small molecules for the treatment of TB. Although several approaches to augmenting standard TB treatment have been proposed, only a few have been explored in detail or advanced to preclinical and clinical studies. Our review focuses on molecular targets and inhibitory small molecules that function within the macrophage or other myeloid cells, on host inflammatory pathways, or at the level of TB-induced lung pathology.

Metformin Adjunctive Therapy Does Not Improve the Sterilizing Activity of the First-Line Antitubercular Regimen in Mice

“…ost-directed therapy (HDT) may offer expanded therapeutic options for improving tuberculosis (TB) treatment (1)(2)(3)(4)(5). Metformin (MetF), an AMP-activated protein kinase (AMPK)-activating drug for type 2 diabetes (DM), was reported to inhibit intracellular growth of mycobacteria by inducing reactive oxygen species and to enhance the efficacy of conventional anti-TB drugs in mouse models of acute and chronic TB; its use was associated with decreased TB severity and improved clinical outcomes in a retrospective analysis of 220 patients with DM and TB (6).…”

The antifibrotic drug pirfenidone promotes pulmonary cavitation and drug resistance in a mouse model of chronic tuberculosis

“…A main strategy for adjunctive HDT of TB involves the modulation of inflammatory pathways to allow reactivation of dormant bacilli within granulomas, thereby enhancing the activity of antimycobacterial drugs (15,16). Given that the antiinflammatory properties of pirfenidone are retained during TB (Figure 1), we explored whether pirfenidone could be used for TB treatment shortening.…”

“…The many pitfalls of using antibiotics, including the inevitable rise of antibiotic resistance, have led to exploration of host-directed therapies (HDTs) as part of the anti-TB arsenal (15)(16)(17)(18). The main strategies used to date, which have involved the enhancement of host antimicrobial mechanisms and cytokine modulation to reduce inflammation and pathology, have yielded varying degrees of success (15,16). In instances where HDTs have been assessed as adjunctive therapies, these have not proved superior to standard TB treatment (19,20).…”

Tuberculosis Vaccines and Prevention of Infection

“…Identification of the immunogenetic factors associated with resistance may lead to novel strategies for immunomodulatory therapy. These strategies might include the use of small-molecule drugs that target host macrophage pathways or vaccines that induce T-cell responses which activate macrophages to kill M. tuberculosis (107).…”