New tricks for old dogs: countering antibiotic resistance in tuberculosis with host-directed therapeutics

Abstract

Despite the availability of Mycobacterium tuberculosis (Mtb) drugs for over 50 years, tuberculosis (TB) remains at pandemic levels. New drugs are urgently needed for resistant strains, shortening duration of treatment, and targeting different stages of the disease, especially for treatment during human immunodeficiency virus co-infection. One solution to the conundrum that antibiotics kill the bacillus yet select for resistance is to target the host rather than the pathogen. Here, we discuss recent progress in so-called 'host-directed therapeutics' (HDTs), focusing on two general mechanistic strategies: (i) HDTs that disrupt Mtb pathogenesis in macrophages and (ii) immunomodulatory HDTs that facilitate protective immune responses that kill Mtb or reduce deleterious responses that exacerbate disease. HDTs hold significant promise as adjunctive therapies in that they are less likely to engender resistance, will likely have efficacy against antibiotic-resistant strains, and may have activity against non-replicating Mtb. However, TB is a complex and variegated disease, and human populations exhibit significant diversity in their immune responses to it, which presents a complicated landscape for HDTs to navigate. Nevertheless, we suggest that a detailed mechanistic understanding of drug action, together with careful selection of disease stage targets and dosing strategies may overcome such limitations and allow the development of HDTs as effective adjunctive treatment options for TB.

Keywords: drug; innate immunity; macrophage; tuberculosis.

Fig. 1. HDT effects on Mtb

(A). Advantages of HDTs against Mtb. (B). Mechanisms of HDT action against Mtb. Some HDTs inhibit host factors required for Mtb pathogenesis (1). Others affect the immune response by augmenting innate immune responses such as autophagy, which can facilitate adaptive responses (2). Still others inhibit deleterious immune responses such as hyperinflammation, which facilitate Mtb pathogensesis (3). Some HDTs induce novel innate or adaptive responses, such as myelopoiesis, or responses that are suppressed by Mtb (4). Finally, in addition to their effects on mammalian factors, some HDTs inhibit bacterial functions that render the pathogen more susceptible to host defenses (5). Note that these mechanisms are not mutually exclusive, and some HDTs have pleiotropic effects and carry out more than one action. Green arrow indicates stimulation and red arrow indicates inhibition.

Fig. 2. TB, autophagy, eicosanoids, and HDTs

Autophagy is critical for macrophage killing of Mtb and critical break points in this pathway are shown. Candidate HDTs are included in shaded boxes at their site of action on the pathways. Abbreviations: AMPK, adenosine monophosphate-dependent protein kinase’ mTORC, mammalian target of rapamycin complex; PI3K, phosphoinositide-3 kinase; ULK1, unc-51 like autophagy activating kinase 1; TBK1, tank-like binding kinase 1; SMERs, small molecule enhancers of rapamycin.

Fig. 3. Metabolic pathways, HDTs, and TB

Lipid and glucose metabolic pathways that modulate TB pathogenesis are depicted. Drugs developed for treating diabetes and hyperlipidemia are included with potential mechanisms of action that could impact Mtb. Abbreviations: AMPK, adenosine monophosphate-dependent protein kinase; LXRα,β, liver X receptors α and β; mTOR, mammalian target of rapamycin; Mtb, Mycobacterium tuberculosis; PPARγ, peroxisome proliferator-activated receptor gamma; TR4, testicular receptor 4; TZD, thiazolidinediones.

Fig. 4. TB, arachidonic acid metabolites, and HDTs

Arachidonic acid metabolites are critical mediators of host defense against Mtb. Candidate HDTs that affect this metabolic pathway are shown in shaded boxes at their site of action on the pathway. (A). In controlled TB disease, the arachidonic acid pathway yields balanced levels of TNF and Type I IFNs, which control infection. (B). In uncontrolled TB disease with elevated levels of LTA4, TNF, and Type I IFNs, eicosanoid signaling is out of balance and favors production of LTA4 at the expense of PGE2. (C). Restoration of equilibrium and control of disease may be achieved with zileuton, which block 5-LO. As a consequence LTA4 levels are reduced and, indirectly, PGE2 levels become elevated, which reduces Type I IFNs and TNF, and permits control of the bacteria. Other drugs such as aspirin or valdecoxib, which inhibit PGE2 production, may be useful when the eicosanoid pathway imbalance favors production of PGE2 at the expense of LTA4. Abbreviations: COX, cyclooxygenase; PGE2, prostaglandin E2; 15LO, 15-lipoxygenase; 5LO, 5-lipoxygenase; LXA4, lipoxin A4; LTA4, leukotriene A4.

Fig. 5. Summary of imatinib effects on Mtb

Imatinib has potent anti-Mtb effects in macrophages and in vivo. Imatinib alters trafficking of Mtb into acidified compartments and thereby facilitates bacterial killing by the macrophage. At doses lower than those used clinically for CML, imatinib induces myelopoiesis and mimics the emergency response to infection, thereby tuning the innate response to facilitate clearance.