Glutamine metabolism inhibitors for TB and TB-HIV: dual action as host-directed therapies with antibacterial activity

结核病和结核病艾滋病毒的谷氨酰胺代谢抑制剂：具有抗菌活性的宿主导向疗法的双重作用

• 批准号: 10456845
• 负责人: WILLIAM Ramses BISHAI
• 金额: $ 81.38万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-16 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10456845
• 关键词: 4T1; Adoptive Transfer; Amino Acids; Animal Model; Anti-Bacterial Agents; Antigens; Antineoplastic Agents; Antitubercular Agents; Bacille Calmette-Guerin vaccination; Biological Availability; CCAAT-Enhancer-Binding Protein-beta; CD8-Positive T-Lymphocytes; Cancer Model; Cells; Clinical; Clinical Trials; Collaborations; Effectiveness; Enzymes; Flow Cytometry; Fostering; Genetic; Glutamate-Ammonia Ligase; Glutamine; Granulocyte Colony-Stimulating Factor; Granuloma; Growth; HIV; HIV/TB; Human; Immune; Immunity; Immunotherapeutic agent; In Vitro; Inflammatory; Lipids; Lung; Lymphoid Cell; Malignant Neoplasms; Measures; Metabolism; Methionine Sulfoximine; Mus; Mycobacterium tuberculosis; Myeloid Cells; Myeloid-derived suppressor cells; Organ; Pharmaceutical Preparations; Population; Prodrugs; Production; Proteins; Purines; Pyrimidine; Resistance; Role; Safety; Seminal; Structure-Activity Relationship; Suppressor-Effector T-Lymphocytes; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; Tryptophan; Tryptophan 2,3 Dioxygenase; Tuberculosis; Virulence; Work; analog; anti-cancer; anticancer activity; antimicrobial; bactericide; base; causal variant; effectiveness evaluation; effector T cell; immune function; improved; inhibitor; macrophage; malignant breast neoplasm; metabolomics; mutant; novel; pathogen; single-cell RNA sequencing; small molecule; tuberculosis drugs; tuberculosis treatment; tumor; tumor microenvironment; tumor progression

PROJECT SUMMARY Myeloid-derived suppressor cells (MDSCs) have emerged as key suppressor cells that inhibit effector immunity both in tumors and in the TB granuloma. In addition, MDSCs have been implicated in HIV progression. We recently demonstrated that high glutamine (Gln) levels in the tumor microenvironment (TME) foster immunotolerance and tumor progression. Furthermore, we showed that inhibitors of glutamine metabolism demonstrate potent anticancer activity in part by reprogramming MDSCs to pro-inflammatory M1-type macrophages. Based on seminal work from Marcus Horwitz at UCLA from 1994-2005 which demonstrated the essentiality of a secreted Mycobacterium tuberculosis (Mtb) glutamine synthase and therapeutic benefit with Gln synthase inhibitors in animal models, we investigated whether high Gln levels in the TB granuloma may similarly suppress host immune function. In a three-way collaboration between a tumor immunobiologist (Powell), a chemist with expertise in Gln metabolism (Slusher), and a TB expert (Bishai), we have evaluated novel Gln metabolism inhibitors that are active anticancer drugs for their effectiveness against TB. In contrast to the earlier work of Horwitz et al., we focused on Gln metabolism inhibitors with improved safety profiles and bioavailability, some of which are currently entering human clinical trials as anticancer agents. We observed potent anti-TB activity with Gln metabolism inhibitors in mice with both reductions in Mtb organ burden and prolongation of survival. This was accompanied by significant reductions in lung MDSCs, a corresponding increase in pro-inflammatory M1-type macrophages, and an increase in activated CD8 T cells in murine TB. Our central scientific premises are that (i) a novel Mtb virulence mechanism is release of excess Gln within granulomas leading to MDSC expansion and an immunotolerant microenvironment that enables pathogen survival and (ii) that Gln metabolism inhibitors may represent a valuable host-directed therapy (HDT) approach for the treatment of TB via MDSC inhibition and enhancement of effector T cell immunity. This application will further define the immunosuppressive roles Gln in the TB granuloma and also investigate a panel of new Gln metabolism inhibitors as TB therapeutics. In Aim 1 we will assess novel Gln metabolism inhibitors for their anti-TB therapeutic efficacy using validated animal models. In Aim 2 we will assess the impact of Gln metabolism inhibitors on myeloid cell populations--including MDSCs--during murine Mtb infection. And in Aim 3 we will evaluate the impact of Gln metabolism inhibitors on lymphoid cell activity during murine Mtb infection. These studies may pave the way for Gln metabolism inhibitors that are currently being developed as anticancer drugs to be repurposed as host-directed therapies for TB and TB-HIV.

项目概要 骨髓源性抑制细胞（MDSC）已成为抑制效应细胞的关键抑制细胞 肿瘤和结核肉芽肿中的免疫力。此外，MDSC 与 HIV 进展有关。 我们最近证明，肿瘤微环境 (TME) 中的高谷氨酰胺 (Gln) 水平会促进 免疫耐受和肿瘤进展。此外，我们发现谷氨酰胺代谢抑制剂 通过将 MDSC 重编程为促炎性 M1 型，证明了有效的抗癌活性 巨噬细胞。基于 1994 年至 2005 年加州大学洛杉矶分校马库斯·霍维茨 (Marcus Horwitz) 的开创性工作，该工作证明了 分泌型结核分枝杆菌 (Mtb) 谷氨酰胺合酶的重要性以及 Gln 的治疗益处 在动物模型中使用合酶抑制剂后，我们研究了结核肉芽肿中高谷氨酰胺水平是否可能类似地 抑制宿主免疫功能。 在肿瘤免疫生物学家 (Powell) 和具有 Gln 专业知识的化学家之间的三方合作中 代谢（Slusher）和结核病专家（Bishai），我们评估了新型谷氨酰胺代谢抑制剂，它们是 活性抗癌药物对结核病有效。与 Horwitz 等人的早期工作相比，我们 专注于具有改进的安全性和生物利用度的谷氨酰胺代谢抑制剂，其中一些是 目前作为抗癌药物进入人体临床试验。 我们在 Mtb 器官减少的小鼠中观察到 Gln 代谢抑制剂具有有效的抗结核活性 负担和延长生存期。伴随着肺 MDSC 的显着减少， 促炎 M1 型巨噬细胞相应增加，活化 CD8 T 细胞增加 鼠结核病。我们的核心科学前提是 (i) 一种新的 Mtb 毒力机制是释放过量的 肉芽肿内的谷氨酰胺导致 MDSC 扩增和免疫耐受微环境，使 病原体存活以及 (ii) Gln 代谢抑制剂可能代表一种有价值的宿主导向疗法 (HDT) 通过抑制 MDSC 和增强效应 T 细胞免疫来治疗 TB 的方法。 该应用将进一步明确 Gln 在结核肉芽肿中的免疫抑制作用，并研究 一组新的谷氨酰胺代谢抑制剂作为结核病治疗剂。在目标 1 中，我们将评估新型 Gln 代谢 使用经过验证的动物模型来评估抑制剂的抗结核治疗功效。在目标 2 中，我们将评估影响 在鼠 Mtb 感染期间，谷氨酰胺代谢抑制剂对骨髓细胞群（包括 MDSC）的影响。和 在目标 3 中，我们将评估 Gln 代谢抑制剂对小鼠 Mtb 期间淋巴细胞活性的影响 感染。这些研究可能为目前正在开发的 Gln 代谢抑制剂铺平道路 抗癌药物将被重新用作结核病和结核病艾滋病毒的宿主导向疗法。