Development of novel anti-TB drugs that inhibit cell wall biosynthesis and respiration

开发抑制细胞壁生物合成和呼吸的新型抗结核药物

• 批准号: 10613897
• 负责人: David Alland
• 金额: $ 62.95万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10613897
• 关键词: Acceleration; Acute; Alleles; Anabolism; Anti-Bacterial Agents; Automobile Driving; Bacteria; Biochemistry; Cause of Death; Cell Respiration; Cell Wall; Cells; Chemicals; Chronic; Clinical; Computer Models; Critical Pathways; Development; Disease; Drug Kinetics; Drug Targeting; Drug resistance; Drug resistance in tuberculosis; Drug resistant Mycobacteria Tuberculosis; Enzymes; Essential Genes; Excretory function; Genes; Genetic; Genomics; Growth; Human; In Vitro; Infection; Infectious Agent; LacZ Genes; Lead; Length; Libraries; Metabolism; Modeling; Multi-Drug Resistance; Multiple Bacterial Drug Resistance; Mus; Mycobacterium tuberculosis; Mycolic Acid; Nitroreductases; Pathway interactions; Pharmaceutical Preparations; Phase; Play; Process; Property; Reporter; Reporter Genes; Resistance; Respiration; Role; Series; Specificity; Structure-Activity Relationship; Therapeutic; Thinness; Time; Toxic effect; Tuberculosis; Vitamin K 2; X-Ray Crystallography; absorption; analog; bacterial metabolism; bactericide; clinically relevant; cytotoxicity; design; drug development; drug efficacy; druggable target; efficacy study; genome sequencing; global health; improved; in vivo; inhibitor; innovation; interest; isoniazid; lead optimization; mortality; mouse model; mutant; novel; novel therapeutics; overexpression; pre-clinical; programs; promoter; respiratory; screening; small molecule; synergism; tuberculosis drugs; tuberculosis treatment; whole genome

ABSTRACT Tuberculosis (TB) is the leading cause of death due to an infectious agent worldwide. The enormous mortality rates associated with this disease are made worse by the emergence of multi-drug resistant bacteria. Thus, new drugs to treat TB are urgently needed. Unfortunately, few new drugs and drug targets have been validated against Mycobacterium tuberculosis (Mtb) despite considerable advances in our understanding of the biochemistry and metabolism of this bacterium. It has become apparent that not all essential metabolic processes represent good drug targets in bacteria. Fortunately, years of drug development efforts have revealed a number of bacterial processes that do appear to contain good targets for antibacterials. These processes include cell wall biosynthesis and cellular respiration. We propose to discover and develop inhibitors that target these druggable processes. To this end, we have developed screens that broadly detect cell wall biosynthesis and respiration inhibitors in Mtb. We have also demonstrated that our screens efficiently identify promising drug leads that are active against Mtb and are specific to these pathways. In our existing CETR, we identified DG167, a compound that inhibited KasA which is an essential enzyme involved in mycolic acid biosynthesis. DG167 has cidal activity against Mtb and it also eliminates persisters in vitro when used in combination with the first line anti- TB drug isoniazid. A CETR screen for respiration inhibitors also successfully identified DG70 and DG77. DG70 inhibited menaquinone biosynthesis, an essential component of cellular respiration in Mtb. DG70 has sterilizing synergy with several key first and second line TB drugs and it has potent activity against persistent forms of Mtb. Finally DG77 was confirmed to also inhibit respiration in Mtb, with the advantage that it had a very high genetic barrier to resistance and strong sterilizing activity in persistent cultures. DG167 has been successfully developed into a highly promising lead with greatly improved PK and activity in an acute mouse model of TB infection. Similarly, DG70 and DG77 have been improved to yield improved ADME as well as in vivo mouse efficacy. Here, we propose to further develop these promising cell wall and respiratory leads into optimized drug leads as pre- clinical candidates. We will also fully characterize existing and ongoing hits from our screens, and optimize the most promising of these into additional leads through our pipeline. Our three specific aims are: 1) Hit to lead and lead optimization of our DG167 analogs that target cell wall biosynthesis in Mtb. 2) Explore and optimize the anti- tubercular drug properties of our DG70 and DG77 compound series that inhibit respiration in Mtb. 3) Evaluate and develop our novel compounds that inhibit cell wall biosynthesis and respiration in Mtb, discovered through our PiniBAC, Pcyd and Pnark2 screens. Together, these three aims will discover, characterize and optimize a variety of compounds with novel targets that inhibit critical pathways in Mtb and greatly advance and accelerate the currently thin pre-clinical pipeline of anti-tuberculars with novel chemical series and new mechanisms of action.

抽象的 结核病（TB）是由于全世界感染力而导致的死亡原因。巨大的死亡率 多药耐药细菌的出现使与该疾病相关的速率变得更糟。因此，新的 迫切需要治疗结核病的药物。不幸的是，很少有新药和药物靶标有验证 尽管我们理解很大，但反对结核分枝杆菌（MTB） 该细菌的生物化学和代谢。显然，并非所有基本代谢 过程代表细菌中的良好药物靶标。幸运的是，多年的药物开发工作已经揭示了 许多确实包含抗菌靶标的细菌过程。这些过程 包括细胞壁生物合成和细胞呼吸。我们建议发现和开发针对目标的抑制剂 这些可药的过程。为此，我们开发了广泛检测细胞壁生物合成的筛选 MTB中的呼吸抑制剂。我们还证明了我们的屏幕有效识别有前途的药物 针对MTB的活性并针对这些途径的引线。在现有的CERT中，我们确定了DG167， 一种抑制KASA的化合物，这是粘液酸生物合成的必不可少的酶。 DG167具有 对MTB的CIDAL活性，当与第一线抗 - 结核病药物异烟肼。呼吸抑制剂的CERT筛选也成功鉴定出DG70和DG77。 DG70 抑制甲喹酮的生物合成，这是MTB细胞呼吸的重要组成部分。 DG70进行了消毒 具有几种关键第一线和第二行TB药物的协同作用，它具有对MTB持续形式的有效活性。 最后，DG77被确认还抑制MTB中的呼吸，其优势是它具有很高的遗传 抵抗性和持久文化中强大的消毒活性的障碍。 DG167已成功开发 在TB感染的急性小鼠模型中，具有极高的铅，大大改善了PK和活性。 同样，DG70和DG77已得到改善，以提高ADME以及体内小鼠的功效。这里， 我们建议进一步发展这些有希望的细胞壁，并将呼吸道引导成优化的药物铅，作为预先的 临床候选人。我们还将完全表征屏幕上现有和正在进行的命中，并优化 通过我们的管道，这些最有前途的最有希望成为其他潜在客户。我们的三个具体目的是：1）击中领导和 靶向MTB中细胞壁生物合成的DG167类似物的铅优化。 2）探索和优化抗 我们的DG70和DG77化合物系列的结核药物特性抑制MTB呼吸。 3）评估 并开发我们的新型化合物，这些化合物抑制了通过MTB中发现的细胞壁生物合成和呼吸 我们的PiniBac，PCYD和PNARK2屏幕。这三个目标将共同发现，表征和优化多样性 具有抑制MTB关键途径的新型靶标的化合物的 目前，具有新型化学系列和新的作用机理的抗链球临界前管道较薄。