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.
Highlights
Tuberculosis (TB) is a leading cause of death worldwide with 10 million new TB cases and 1.6 million deaths in 2017 alone [1]
To investigate whether cysteamine had an anti-microbial activity against Mycobacterium tuberculosis (Mtb) in macrophages, THP-1 monocyte-derived macrophages were infected with Mtb H37Rv and treated with cystamine and cysteamine at concentrations compatible to those achieved in vivo [16]
In this study, using a panel of in vitro experimental assays, we show that cysteamine and cystamine, two known inhibitors of transglutaminase 2 (TG2), can restrict Mtb replication in macrophages infected with the Mtb H37Rv reference strain and a panel of clinical isolates representative of different phylogeographic lineages
Summary
Tuberculosis (TB) is a leading cause of death worldwide with 10 million new TB cases and 1.6 million deaths in 2017 alone [1]. Despite the introduction of new drugs, therapeutic regimens of MDR-TB and XDR-TB patients show poor success rates that rarely exceed 50% in high-burden countries [4]. These regimens are very expensive; combining direct and indirect costs, in EU states and the US, the average cost for an MDR-TB patient is five to six times higher than a drug-susceptible patient and increases up to 20 times for XDR-TB [2, 5]. These high costs associated with the treatment of drug-resistant TB pose a major burden to many countries, with relevant health, social, and economic consequences [2]
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