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.

中文翻译：

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转谷氨酰胺酶2的抑制作为针对结核分枝杆菌的潜在宿主定向疗法。

宿主定向疗法（HDTs）正在成为治疗耐药性结核病（TB）的潜在有效支持。在我们最近的报道表明转谷氨酰胺酶2（TG2）的遗传和药理学抑制作用限制了结核分枝杆菌（Mtb）在巨噬细胞中的复制后，我们旨在研究TG2抑制剂胱胺和半胱胺作为针对结核病的HDT的潜力。我们显示，当以等摩尔浓度提供时，半胱胺和胱胺都限制了感染巨噬细胞中Mtb的复制，而当直接施用于Mtb培养物时，则没有发挥任何抗菌活性。有趣的是 感染分化的THP-1 mRFP-GFP-LC3B细胞，然后测定自噬中间体pH分布（AIPD）表明，胱胺抑制自噬通量，同时限制Mtb复制。此外，在被一组属于不同谱系的Mtb临床菌株感染的原代巨噬细胞中，胱胺和半胱胺均具有相似的抗菌活性。在人肉芽肿样结构（GLS）的体外模型中对半胱胺和胱胺活性的评估进一步证实了这些药物具有限制Mtb复制和减小GLS大小的能力。在人类单核细胞衍生的巨噬细胞和GLS模型中，与二线抗结核药物（阿米卡星）协同作用的TG2抑制剂的抗菌活性。总体，