MmpL3 as a target for novel anti-TB agents

MmpL3 作为新型抗结核药物的靶点

• 批准号: 9276565
• 负责人: Mary Jackson
• 金额: $ 51.36万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276565
• 关键词: AIDS/HIV problem; Accounting; Acquired Immunodeficiency Syndrome; Adverse reactions; Alpha Cell; Anti-Retroviral Agents; Antitubercular Agents; Antiviral Agents; Bacillus (bacterium); Binding; Binding Sites; Biological Assay; Cause of Death; Cells; Cessation of life; Chemicals; Complement; Cytochrome P450; Cytoplasm; Development; Drug Interactions; Drug Kinetics; Drug toxicity; Enzymes; Extreme drug resistant tuberculosis; Fatty Acids; Gene Silencing; Genus Mycobacterium; Goals; Grant; Growth; HIV; Human; Immunosuppression; In Situ; In Vitro; Joints; Kinetics; Laboratories; Libraries; Maps; Measurement; Measures; Membrane; Membrane Proteins; Methods; Mus; Mycobacterium smegmatis; Mycobacterium tuberculosis; Mycolic Acid; Pharmaceutical Preparations; Phase II Clinical Trials; Physiological; Proteins; Proteomics; Proton-Motive Force; Public Health; Recombinants; Regimen; Reporting; Research Project Grants; Research Proposals; Resistance; Series; Surface Plasmon Resonance; Testing; Therapeutic; Transcript; Tuberculosis; United States National Institutes of Health; Urea; Validation; Work; assay development; base; biological adaptation to stress; cell envelope; drug candidate; extensive drug resistance; genetic approach; genome sequencing; in vitro Assay; in vivo; inhibitor/antagonist; interest; killings; mutant; new therapeutic target; novel; novel therapeutic intervention; periplasm; prevent; process optimization; promoter; public health relevance; scaffold; screening; small molecule; small molecule inhibitor; targeted treatment; therapeutic target; treatment duration; tuberculosis drugs; tuberculosis treatment; whole genome

 DESCRIPTION (provided by applicant): Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major public health problem worldwide and the most common presenting illness among people living with HIV, including those who are taking antiretroviral treatment. TB is also the leading cause of death among people living with HIV, accounting for one in four HIV/AIDS-associated deaths. The development of shorter and simpler drug regimens that are well tolerated, effective against multiple and extensively drug-resistant (MDR/XDR) Mtb and appropriate for joint TB/HIV treatment is urgently needed. The return of interest in whole cell-based screens to identify novel anti-TB compound has led to the identification of a number of promising inhibitors. Intriguingly, several of them including the TB drug candidate SQ109 have been reported to kill Mtb through their inhibitory activity on the mycolic acid transporter, MmpL3. Mycolic acids are abundant long chain (C60-C90) fatty acids synthesized in the cytoplasm that populate both the inner and the outer leaflets of the outer membrane of all mycobacteria; by preventing mycolic acids from being exported to the periplasmic space, the inhibition of MmpL3 prevents the formation of the outer membrane of Mtb. The fact that multiple chemical scaffolds block the growth of Mtb through the apparent inhibition of MmpL3 may reflect the unusual vulnerability and "druggability" of this transporter. Alternatively, our preliminary results have led us to question the direct mechanism of inhibition of MmpL3 by some of these compounds. Thus, in spite of the growing interest in MmpL3 as a novel therapeutic target and owing to the technical challenges associated with the development of transport assays for this large membrane protein, MmpL3 has not yet been validated as the direct target of any Mtb inhibitor. The critical need for novel therapeutic approaches to treat MDR/XDR-Mtb infections and the importance of understanding the mode of action of small molecule inhibitors to drive their optimization process make the validation of MmpL3 as a novel drug target and the development of inhibition assays for this transporter a high priority. This proposal is to establish the therapeutic potential of MmpL3 by determining its vulnerability (i.e., how much inhibition of the target's activity is required to block bacterial growth) in vitro and in vivo (Aim 1), to develop the whole cell-based and cell-free assays required for the screening, validation and optimization of inhibitors of this transporter (Aim 2) and to provide proof-of-concept of its druggability by small molecule inhibitors (Aim 3).

 描述（由适用提供）：结核分枝杆菌（MTB）引起的结核病（TB）仍然是全世界的主要公共卫生问题，并且是艾滋病毒感染者中最常见的疾病，包括接受抗逆转录病毒治疗的患者。结核病也是艾滋病毒患者中死亡的主要原因，占艾滋病毒/艾滋病相关的四分之一的死亡。迫切需要耐受耐受性的较短，更简单的药物方案，对多种和广泛的药物耐药性（MDR/XDR）MTB有效，​​并且紧急需要用于联合结合TB/HIV治疗。对整个细胞筛查识别新型抗TB化合物的兴趣回报导致了许多有望抑制剂的识别。有趣的是，据报道其中一些包括TB药物SQ109通过其对霉菌酸转运蛋白MMPL3的抑制活性杀死MTB。尼粒酒酸是在细胞质中合成的丰富的长链（C60-C90），这些脂肪酸在所有菌群的外膜的内部和外膜中均填充了脂肪酸；通过防止霉菌酸出口到外围空间，MMPL3的抑制可防止MTB外膜的形成。多个化学支架通过MMPL3明显抑制阻止MTB的生长这一事实可能反映了该转运蛋白的异常脆弱性和“药物可药用”。另外，我们的初步结果使我们质疑其中一些化合物抑制MMPL3的直接机制。尽管对MMPL3作为一种新型治疗靶点的兴趣日益增长，并且由于与该大型膜蛋白的运输评估相关的技术挑战，但MMPL3尚未被验证为任何MTB抑制剂的直接靶标。对治疗MDR/XDR-MTB感染的新型治疗方法的批判性需求以及理解小分子抑制剂推动其优化过程的作用方式的重要性，使MMPL3成为一种新型药物靶标，并发展了该转运蛋白的抑制主张的发展。该建议是通过确定其脆弱性来确定MMPL3的治疗潜力（即 需要多少抑制目标活性以阻断细菌的生长）体外和IN Vivo（AIM 1），开发筛选，验证和优化该转运蛋白抑制剂所需的整个基于细胞的和无细胞的测定（AIM 2），并通过小分子抑制剂提供对其可药用的概念证明（AIM 3）。