Opportunities for Overcoming Mycobacterium tuberculosis Drug Resistance: Emerging Mycobacterial Targets and Host-Directed Therapy

Abstract

The ever-increasing incidence of drug-resistant Mycobacterium tuberculosis infections has invigorated the focus on the discovery and development of novel treatment options. The discovery and investigation of essential mycobacterial targets is of utmost importance. In addition to the discovery of novel targets, focusing on non-lethal pathways and the use of host-directed therapies has gained interest. These adjunctive treatment options could not only lead to increased antibiotic susceptibility of Mycobacterium tuberculosis, but also have the potential to avoid the emergence of drug resistance. Host-directed therapies, on the other hand, can also reduce the associated lung pathology and improve disease outcome. This review will provide an outline of recent opportunities.

Host-Directed Therapy as a Novel Treatment Strategy to Overcome Tuberculosis: Targeting Immune Modulation

“…Inhibition of mammalian target of rapamycin (mTOR), activation of autophagy Palucci et al [123] Torfs et al [124] Metformin Reduce phosphorylation of mTOR and P 70s6k , activation of autophagy Singhal et al [125] Carbamazepine, Valproic acid Activation of autophagy Schiebler et al [126] Statin Inhibition of cholesterol in phagosomal membrane, activation of autophagy Parihar et al [127] Nonsteroidal anti-inflammatory drugs (NSAIDs) (diclofenac and ibuprofen)…”

“…However, the use of rapamycin as HDT is limited in TB because of obstacles related to adverse effects. Another drawback of using rapamycin in TB-infection is that rapamycin is metabolized by the hepatic enzymes CYP3A4, which is induced by the key first-line drug rifampicin [123,124]. Another candidate of HDT is metformin (Table 1), which is a common drug for treating diabetes mellitus type 2.…”

Looking beyond Typical Treatments for Atypical Mycobacteria

“…Traditional antibiotics act directly on the pathogen by killing or inhibiting its growth. However, by targeting the host factors necessary for the bacteria to survive or replicate, it is possible to control the infection without inducing bacterial resistance and, at the same time, to minimize the dosage of traditional agents [206,207]. Host-directed therapies (HDT) can modulate specific pathways or mechanisms, stimulating, for instance, the host immune system to more efficiently combat the infection, or reducing the symptoms caused by exacerbated inflammation [206,207].…”

“…This results in the isolation of the pathogen inside autophagosomes, which are fused with lysosomes, resulting in the digestion of the pathogen and the induction of an adaptive immune response [217]. Given the fact that mycobacteria naturally inhibit the phagosome-lysosome fusion [24], the induction of autophagy is an appealing target to HDT [207]. Studies done with nonpathogenic mycobacteria have yielded contradictory results, and it is not clear whether mycobacteria induce or inhibit macrophage autophagy, and what the role of this process is in mycobacterial growth containment.…”

“…[217,219]. Anticonvulsant drugs, EGFR inhibitors, and even the role of vitamin D in promoting autophagy have been studied against Mtb [207]. In M. avium, lactoferricin, in particular, the D-enantiomer of LFcin17-30, leads to the intramacrophagic death of the mycobacteria by inducing phagosomal maturation and autophagy, with increased lysosomes and autophagosomes [171].…”