Rationale

Host-directed therapeutics for Mycobacterium tuberculosis (Mtb) offer potential strategies for combatting antibiotic resistance and for killing non-replicating bacilli. Phenylbutyrate, a partially selective histone-deacetylase (HDAC) inhibitor, was previously shown to control Mtb growth and alter macrophage inflammatory pathways at 2–4 mM concentrations.

Objective

To identify a more potent and selective HDAC inhibitor that modulates macrophage responses to mycobacteria and has direct antibacterial effects against Mtb.

Methods

We used cellular approaches to characterize the role of pharmacologic inhibition of HDAC3 on Mtb growth and Mtb-induced peripheral and alveolar macrophage immune functions.

Measurements and main results

RGFP966, an HDAC3 inhibitor, controlled Mtb, BCG and M. avium growth directly in broth culture and in human peripheral blood monocyte-derived and alveolar macrophages with an MIC50 of approximately 5–10 μM. In contrast, RGFP966 did not inhibit growth of several other intracellular and extracellular bacteria. We also found that RGFP966 modulated macrophage pro-inflammatory cytokine secretion in response to Mtb infection with decreased IL6 and TNF secretion.

Conclusions

We identified a potent and selective small molecule inhibitor of HDAC3 with direct antimicrobial activity against Mtb and modulation of macrophage signaling pathways.

中文翻译：

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HDAC3 抑制剂 RGFP966 在结核分枝杆菌感染期间控制细菌生长并调节巨噬细胞信号传导

基本原理

结核分枝杆菌(Mtb)的宿主导向疗法为对抗抗生素耐药性和杀死非复制杆菌提供了潜在的策略。Phenylbutyrate 是一种部分选择性的组蛋白脱乙酰酶 (HDAC) 抑制剂，先前已显示在 2-4 mM 浓度下可控制 Mtb 生长并改变巨噬细胞炎症通路。

客观的

鉴定一种更有效、更具选择性的 HDAC 抑制剂，可调节巨噬细胞对分枝杆菌的反应，并对 Mtb 具有直接的抗菌作用。

方法

我们使用细胞方法来表征 HDAC3 的药理学抑制对 Mtb 生长和 Mtb 诱导的外周和肺泡巨噬细胞免疫功能的作用。

测量和主要结果

RGFP966 是一种 HDAC3 抑制剂，可直接在肉汤培养和人外周血单核细胞衍生和肺泡巨噬细胞中控制 Mtb、BCG 和鸟分枝杆菌的生长，MIC50 约为 5–10 μM。相反，RGFP966 不抑制其他几种细胞内和细胞外细菌的生长。我们还发现 RGFP966 调节巨噬细胞促炎细胞因子分泌以响应 Mtb 感染，减少 IL6 和 TNF 分泌。

结论

我们鉴定了一种有效的、选择性的 HDAC3 小分子抑制剂，具有对 Mtb 的直接抗菌活性和巨噬细胞信号通路的调节。