Inhibition of Transglutaminase 2 as a Potential Host-Directed Therapy Against Mycobacterium tuberculosis

Abstract

Host-directed therapies (HDTs) are emerging as a potential valid support in the treatment of drug-resistant tuberculosis (TB). Following our recent report indicating that genetic and pharmacological inhibition of transglutaminase 2 (TG2) restricts Mycobacterium tuberculosis (Mtb) replication in macrophages, we aimed to investigate the potentials of the TG2 inhibitors cystamine and cysteamine as HDTs against TB. We showed that both cysteamine and cystamine restricted Mtb replication in infected macrophages when provided at equimolar concentrations and did not exert any antibacterial activity when administered directly on Mtb cultures. Interestingly, infection of differentiated THP-1 mRFP-GFP-LC3B cells followed by the determination of the autophagic intermediates pH distribution (AIPD) showed that cystamine inhibited the autophagic flux while restricting Mtb replication. Moreover, both cystamine and cysteamine had a similar antimicrobial activity in primary macrophages infected with a panel of Mtb clinical strains belonging to different phylogeographic lineages. Evaluation of cysteamine and cystamine activity in the human ex vivo model of granuloma-like structures (GLS) further confirmed the ability of these drugs to restrict Mtb replication and to reduce the size of GLS. The antimicrobial activity of the TG2 inhibitors synergized with a second-line anti-TB drug as amikacin in human monocyte-derived macrophages and in the GLS model. Overall, the results of this study support the potential usefulness of the TG2-inhibitors cysteamine and cystamine as HDTs against TB.

Cysteamine with In Vitro Antiviral Activity and Immunomodulatory Effects Has the Potential to Be a Repurposing Drug Candidate for COVID-19 Therapy

“…Although some scientific findings suggest that autophagy plays an important role in viral replication and pathogenesis, its role during SARS-CoV-2 infection remains to be completely defined. In keeping with this notion, we showed that cysteamine impairs the bacterium replication in Mtb-infected macrophages by inhibiting autophagy in vitro [ 14 ]. Thus, it would be important to explore in the future whether the cysteamine effects on SARS-CoV-2 are related to the modulation of cell autophagy, and how these events affect the host cell antiviral properties.…”

“…Since cysteamine is commonly used as a TG2 inhibitor [ 10 , 13 , 14 ], we investigated whether TG2 could play a role on SARS-CoV-2 replication. Firstly, we used Z-DON, a specific inhibitor of the transamidating activity of TG2 [ 13 ], in the CPE inhibition assay in Vero E6 cells.…”

“…It increases Pseudomonas aeruginosa sensitivity to antibiotics exerting activity against different Plasmodium species, and has mucolytic-antimicrobial activity in cystic fibrosis [ 12 ]. Recently, we showed that the pharmacological inactivation of TG2 by cysteamine enhances the anti-mycobacterial properties of Mycobacterium tuberculosis (Mtb)-infected macrophages acting as a host-directed agent [ 13 , 14 ]. Cysteamine exhibited an improved clearance of, and resistance to, Pseudomonas aeruginosa in both patients and mice with CF [ 5 ].…”

The Dark Side of the Covid-19 Treatments on Mycobacterium Tuberculosis Infection

“…31 In the last decades, to deal with the emergence of Mtb strains resistant anti-TB drugs (MDR/RR-Mtb and XDR-Mtb), a novel approach has been proposed targeting the host and so named host directed therapies (HDTs). [32][33][34][35] HDTs can support antimycobacterial host response at different stages: a) perturbating granuloma integrity to enhance drug penetration; b) modifying autophagy or phagosome maturation to increase intracellular killing; c) promoting cell-mediated response; d) inducing antimicrobial peptides and controlling inflammation response by avoiding tissue damage. 36 While the use of HDTs seem to support anti-TB treatment in symptomatic individuals, 37 no data nor anecdotal knowledge support the use of such therapies in people with asymptomatic or subclinical infection.…”

Structures of Human Transglutaminase 2: Finding Clues for Interference in Cross-linking Mediated Activity

“…Owing to its biologically and pathogenically important functions, TGase2 has been considered a major therapeutic target for the treatment of many human diseases caused by dysregulated TGase2 [29,[53][54][55][56]. The aim of this review was to summarize the recent progress in the structural studies of TGase2, which can aid in the development of drugs targeting this enzyme.…”