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：作为具有抗菌活性的宿主导向疗法的双重作用

• 批准号: 10686328
• 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/10686328
• 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; Macrophage; 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; Sorting; Structure-Activity Relationship; Suppressor-Effector T-Lymphocytes; T-Cell Activation; Testing; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; Tryptophan; Tryptophan 2,3 Dioxygenase; Tuberculosis; Virulence; Work; analog; anti-cancer; anticancer activity; antimicrobial; bactericide; causal variant; effectiveness evaluation; effector T cell; immune function; improved; inhibitor; malignant breast neoplasm; metabolomics; mutant; novel; pathogen; single-cell RNA sequencing; small molecule; tuberculosis drugs; tuberculosis granuloma; 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.

项目总结 髓系来源的抑制细胞(MDSCs)已成为抑制效应器的关键抑制细胞 肿瘤和结核肉芽肿中均有免疫反应。此外，骨髓间充质干细胞还与艾滋病毒的进展有关。 我们最近证明，肿瘤微环境(TME)中的高谷氨酰胺(Gln)水平有助于 免疫耐受与肿瘤进展。此外，我们还发现谷氨酰胺新陈代谢的抑制剂 显示出强大的抗癌活性，部分是通过将MDSCs重新编程为促炎的M1型 巨噬细胞。基于加州大学洛杉矶分校Marcus Horwitz在1994-2005年间的开创性工作，该工作证明了 分泌型结核分枝杆菌谷氨酰胺合成酶的必要性及谷氨酰胺的疗效 在动物模型中，我们研究了结核肉芽肿中高谷氨酸氨基转移酶水平是否类似 抑制宿主免疫功能。 在肿瘤免疫生物学家(鲍威尔)、精通Gln的化学家之间的三方合作中 (Slusher)和结核病专家(Bishai)，我们评估了新的谷氨酰胺代谢抑制剂，这些药物是 活性抗癌药物对结核病的有效性。与Horwitz等人早期的工作不同，我们 重点关注安全性和生物利用度提高的谷氨酰胺代谢抑制剂，其中一些是 目前正在作为抗癌剂进入人体临床试验。 我们观察到谷氨酰胺代谢抑制剂对结核分枝杆菌两种器官减少的小鼠都有很强的抗结核活性。 生存的负担和延长。伴随而来的是肺MDSCs的显著减少， 促炎症的M1型巨噬细胞相应增加，活化的CD8T细胞增加 小鼠结核病。我们的主要科学前提是：(I)一种新的结核分枝杆菌毒力机制是释放过量的 肉芽肿内的Gln导致MDSC扩张和免疫耐受微环境 病原体存活和(Ii)谷氨酰胺代谢抑制剂可能是一种有价值的宿主导向治疗(HDT)。 抑制MDSC和增强效应性T细胞免疫治疗结核病的探讨 这项应用将进一步确定谷氨酰胺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的治疗药物。在目标1中，我们将评估新的谷氨酰胺代谢 在经过验证的动物模型中研究其抗结核病治疗效果的抑制剂。在目标2中，我们将评估影响 在小鼠结核分枝杆菌感染期间，谷氨酰胺代谢抑制剂对包括MDSCs在内的髓系细胞群体的影响。和 在目标3中，我们将评估谷氨酰胺代谢抑制剂对小鼠结核杆菌感染过程中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谷氨酰胺代谢抑制剂铺平道路 抗癌药物将被重新用于治疗结核病和结核病-艾滋病毒的宿主导向疗法。

项目成果

Structure-directed identification of pyridine-2-methylamine derivatives as MmpL3 inhibitors for use as antitubercular agents.

• DOI: 10.1016/j.ejmech.2023.115351
• 发表时间: 2023-04
• 期刊: European journal of medicinal chemistry
• 影响因子: 6.7
• 作者: Yu Wen;S. Lun;Yuxue Jiao;Wei Zhang;Ting Liu;Fan Yang;Jie Tang;W. Bishai;Lifang Yu