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.

项目摘要 骨髓源性抑制细胞（MDSC）已成为抑制效应细胞增殖的关键抑制细胞。 在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）中高水平的谷氨酰胺（Gln）可促进肿瘤微环境（TME）的形成。 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， 巨噬细胞基于1994-2005年加州大学洛杉矶分校马库斯·霍维茨的开创性工作， 分泌型结核分枝杆菌谷氨酰胺合酶的必要性和谷氨酰胺的治疗益处 在动物模型中，我们研究了结核肉芽肿中的高谷氨酰胺水平是否可能类似于 抑制宿主免疫功能。 在肿瘤免疫生物学家（鲍威尔），具有谷氨酰胺专长的化学家 代谢（Slusher）和结核病专家（Bishai），我们评估了新的谷氨酰胺代谢抑制剂， 活性抗癌药物对结核病的有效性。与Horwitz等人的早期工作相反，我们 专注于具有改善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 目前正作为抗癌药物进入人体临床试验。 我们在小鼠中观察到谷氨酰胺代谢抑制剂的有效抗结核活性， 负担和延长生存期。这伴随着肺MDSC的显著减少， 促炎性M1型巨噬细胞相应增加，活化的CD 8 T细胞增加， 鼠结核病我们的中心科学前提是：（i）一种新的结核分枝杆菌毒力机制是释放过量的 肉芽肿内的谷氨酰胺导致MDSC扩增和免疫耐受微环境， 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） 通过MDSC抑制和增强效应T细胞免疫治疗TB的方法。 本研究将进一步明确谷氨酰胺在结核肉芽肿中的免疫抑制作用， 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，我们将评估新型谷氨酰胺代谢 使用经验证的动物模型，评估抑制剂的抗TB治疗功效。在目标2中，我们将评估 谷氨酰胺代谢抑制剂对骨髓细胞群-包括MDSC-在鼠结核分枝杆菌感染。和 在目的3中，我们将评估谷氨酰胺代谢抑制剂对小鼠Mtb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Gln代谢抑制剂铺平道路， 抗癌药物被重新用作结核病和结核病-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