Inhibitors of CoA biosynthesis as novel antitubercular and antistaphylococcal agents

作为新型抗结核和抗葡萄球菌药物的 CoA 生物合成抑制剂

基本信息

批准号：
10113512
负责人：
Erick Strauss
金额：
$ 13.1万
依托单位：
STELLENBOSCH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-05 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10113512
关键词：
Address Adherence Aerobic Anabolism Anaerobic Bacteria Anti-Bacterial Agents Antibiotics Antitubercular Agents Back Bacteria Binding Biochemical Biological Assay Bypass Cells Cellular Assay Clinical Coenzyme A Communicable Diseases Communities Cytosine Data Developing Countries Development Doctor of Philosophy Drug Design Drug Targeting Drug resistance Drug resistance in tuberculosis Energy Metabolism Energy-Generating Resources Enzymes Evaluation Fermentation Foundations Genetic study Goals Growth HIV Health Hospitals Human In Situ In Vitro Infection Infectious Agent International Life Measures Metabolic Activation Metabolism Modeling Mus Mycobacterium tuberculosis Mycobacterium tuberculosis H37Rv Natural Products Nosocomial Infections Organism Pathway interactions Physiological Prevalence Process Prodrugs Proteins Reaction Resistance Respiration Ribose Series South Africa Specificity Staphylococcus aureus Structure Structure-Activity Relationship System Testing Therapeutic Agents Tuberculosis Universities Virulence analog bactericide base cell envelope chronic infection co-infection cofactor cytotoxicity design enzyme activity enzyme pathway experimental study fatty acid biosynthesis genetic resistance improved in vivo inhibitor/antagonist interest macrophage mutant novel pathogen phosphonate prevent priority pathogen small molecule small molecule inhibitor small molecule therapeutics targeted agent tuberculosis treatment

项目摘要

PROJECT SUMMARY/ABSTRACT Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), continues to be one of the world’s deadliest infectious diseases because of several factors, including a) poor adherence to the long-term multidrug therapy, b) latent (or persistent) infection, c) co-infection with HIV and d) drug-resistant Mtb strains that are unaffected by current TB therapies. Similarly, Staphylococcus aureus was recently listed by the WHO as a “high priority” pathogen in regards to new antibiotic development, due to its increasing prevalence as a major infectious agent both in hospitals and in the community, and to increased virulence and rising resistance against current antistaphylococcal agents. The biosynthesis of coenzyme A (CoA), an essential cofactor relevant to several metabolic processes, contains an emerging set of targets for antibacterial drug design. Small molecule inhibitors of this pathway have shown activity in a cell-based model of latent TB, increasing interest in this set of targets as a potential means attacking the latent pathogen. Similarly, CoA biosynthesis in S. aureus has recently been associated with maintaining the organism under anaerobic conditions, a model for persistent infections. The broad, long-term objective of this project is to develop inhibitors of CoA biosynthesis, which act on the PPCS enzyme activity of Mtb and S. aureus, that show whole cell activity under a range of conditions and potential for further development as clinically useful agents that could be used in combination treatments. This goal has strong foundations in results from in vitro genetic studies demonstrating the vulnerability of the target, and in vivo experiments showing that depletion of PPCS activity is bactericidal and prevents a robust Mtb infection in mice. In S. aureus, a natural product that targets PPCS activity shows highly selective whole cell activity. These results suggest that the PPCS activity is a highly promising target that is tractable to inhibition by small molecules. To develop new whole cell active compounds, we are proposing inhibitor structures based on a well-established strategy that has successfully been used to prepare inhibitors of mechanistically similar enzymes, giving rise to compounds that also showed excellent whole cell activity against Mtb and S. aureus. In addition, we are proposing complementary metabolic activation and prodrug approaches to address the known challenge of preparing compounds that are able to cross the Mtb cell envelope. We will pursue this objective through three Specific Aims: 1) Design and synthesis of Pan-CMP mimics as PPCS inhibitors; 2) Biochemical evaluation of metabolic activation and PPCS inhibition of Aim 1 compounds; and 3) Evaluation of PPCS inhibitors in models of actively growing and persistent Mtb and S. aureus. These aims are formulated to systematically optimize the structure of the inhibitors and to follow their on-target activity and selectivity through enzymatic and whole cell assays, the latter including tests against wild-type Mtb and S. aureus and mutant Mtb strains (to show target specificity), models of latent/persistent growth for both Mtb and S. aureus, and an ex vivo macrophage model (in the case of Mtb).

项目摘要/摘要由结核分枝杆菌（MTB）引起的结核病（TB）仍然是世界上之一最致命的传染病是由于多种因素，包括a）长期依从性不佳多药疗法，b）潜在（或持续性）感染，c）与HIV和D）耐药的MTB菌株共同感染不受当前结核病疗法的影响。同样，世卫组织最近列出了金黄色葡萄球菌作为对新抗生素发育的“高优先级”病原体，因为它的患病率增加了医院和社区中的主要传染毒剂，以及增加病毒和抗药性的增加针对当前的抗炎球菌。辅酶A（COA）的生物合成，一种必需的辅助因子与几个代谢过程相关，其中包含一组新兴的抗菌药物设计靶标。该途径的小分子抑制剂已显示在基于细胞的潜在TB模型中的活性，增加了对这组目标的兴趣是一种潜在的意思，意味着攻击潜在病原体。同样，COA生物合成金黄色葡萄球菌最近与在厌氧条件下保持生物体有关，这是一个模型持续感染。该项目的广泛长期目标是开发COA生物合成的抑制剂，对MTB和金黄色葡萄球菌的PPCS酶活性作用，在一系列范围内显示了全细胞活性条件和进一步开发的潜力作为临床上有用的药物，可用于组合治疗。该目标在体外遗传研究的结果中具有很大的基础，证明了靶标的脆弱性和体内实验，表明PPCS活性的耗竭是杀菌性和防止小鼠中强大的MTB感染。在金黄色葡萄球菌中，针对PPCS活性的天然产物表现高选择性全细胞活性。这些结果表明，PPCS活动是一个高度有希望的目标小分子可抑制。要开发新的全细胞活性化合物，我们正在提议基于公认策略的抑制剂结构已成功用于制备抑制剂机械相似的酶，引起化合物，这些化合物也表现出极好的整体活性反对MTB和S.金黄色葡萄球菌。此外，我们提出了完整的代谢激活和前药解决能够越过MTB单元的化合物的已知挑战的方法信封。我们将通过三个具体目标来追求这一目标：1）pan-cmp的设计和合成模仿PPC抑制剂； 2）代谢激活和PPC抑制AIM的生化评估1 化合物； 3）评估PPC抑制剂在积极生长和持续的MTB和S的模型中。金黄色葡萄酒。这些目标是为了系统地优化抑制剂的结构并遵循其目标通过酶和全细胞测定法，后者的靶向活性和选择性，后者包括针对的测试野生型MTB和S.金黄色葡萄球菌和突变体MTB菌株（显示目标特异性），潜在/持续的模型 MTB和金黄色葡萄球菌的生长以及离体巨噬细胞模型（在MTB的情况下）。