Oral Metallo-Beta-Lactamase Inhibitors: Exploiting Reaction Mechanisms

口服金属-β-内酰胺酶抑制剂：利用反应机制

• 批准号: 10618795
• 负责人: ROBERT A. BONOMO
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618795
• 关键词: Achievement; Animal Model; Antibiotics; Argentina; Bacteria; Binding; Binding Proteins; Biological; Biological Availability; Carbapenems; Carboxylic Acids; Cephalosporinase; Cephalosporins; Chemicals; Clinical; Collaborations; Coupled; Development; Evaluation; Exhibits; Extended-spectrum β-lactamase; Formulation; Foundations; Gastrointestinal tract structure; Goals; Gram-Negative Bacteria; Hydrolysis; Imipenem; Industry; Infection; Intestinal Absorption; Investigation; Investigational New Drug Application; Investigational Therapies; Knowledge; L Forms; Lactams; Lead; Mediating; Medical; Meropenem; Metabolic; Metals; Methods; Military Personnel; Modeling; Mus; Nature; Oral; Osteomyelitis; Patients; Penicillins; Predisposition; Prodrugs; Program Development; Property; Public Health; Reaction; Research Institute; Resistance; Scientist; Series; Serine; Serum; Skin Tissue; Sulfhydryl Compounds; Testing; Therapeutic; Thigh structure; Uruguay; Veterans Health Administration; Wound Infection; absorption; acyl group; alternative treatment; bactericide; beta-Lactamase; beta-Lactams; carbapenem resistance; carbapenemase; clinical application; comparison control; cytotoxicity; design; drug development; drug discovery; healing; high reward; high risk; improved; in vitro testing; inhibitor; innovation; joint infection; meter; mouse model; novel; novel therapeutics; pathogen; pharmacokinetics and pharmacodynamics; programs; soft tissue; stem; thioester; wound

Gram-negative pathogens producing metallo-β-lactamases, MBLs, are a significant threat to our public health as treatment options against bacteria possessing these resistance determinants are extremely limited. In general, MBLs are the most worrisome carbapenemases, inactivating “last resort” β-lactams (e.g., imipenem and meropenem) and resist all commercially available β-lactamase inhibitors (BLIs). The main challenge in MBL inhibitor design is exploiting the reaction mechanism as it relates to the structural diversity of the 3 distinct subclasses (B1, B2, and B3). Based on this approach, our consortium has successfully designed a series of innovative compounds, bisthiazolidines (BTZs) and thiazolidines (TZs), inspired on a non-β-lactam “penicillin core” decorated with specific metal binding groups. To date, BTZs and TZs are unique potent, non- toxic, “cross-class” MBL inhibitors. Recently, we determined the structural basis of their inhibitory action, and their microbiological activity (bactericidal when combined with a carbapenem). This inspires confidence in the ability of BTZs and TZs to be effective against MBL producing Gram-negative bacteria. Interestingly, novel TZs exhibit similar properties and potencies and in certain cases are superior to BTZs. The overarching objectives of this project are to embark upon a “high risk-high reward” program in drug discovery to develop an effective oral MBL inhibitor that is absorbed sufficiently from the gastrointestinal (GI) tract and can be partnered with an oral carbapenem, tebipenem pivoxil (Tbp-Pvx). We are co-opting an established strategy, the addition of a pivoxil group, which has been successful in at least two commercial formulations (cefditoren pivoxil and tebipenem pivoxil) and adapting it to our developmental compounds (BTZs and TZs). Since parenteral inhibitors for serine carbapenemases are already in clinical use (e.g., avibactam, relebactam and vaborbactam) and only a few truly MBL inhibitors are in development (QPX7728 and taniborbactam), our unique and specific formulation will address an unmet medical need, i.e. that of an oral cross-subclass MBL inhibitor. By the nature of its components, Tbp-Pvx is also intended to be stable against extended-spectrum β-lactamases (ESBLs) and class C cephalosporinases (AmpCs), which are resistance determinants often present in MBL-producing strains. Additionally, we will mitigate the problems associated with cephalosporins (resistance selection). As a lead compound, we have identified a potent BTZ (L syn CS319) that effectively lowers MICs to within the susceptible range when paired with a carbapenem. As an alternative, we have also synthesized potent TZ derivatives. We propose to develop the first oral carbapenem and MBL inhibitor formulation to be considered for development that overcomes difficult to treat carbapenem resistant infections mediated by MBLs. Our experimental evaluations stem from close partnership with scientists in Argentina and Uruguay and will involve a closer collaboration with the Wound Infections Department (WID) and the Experimental Therapeutics (ET) Branch of the Walter Reed Army Institute of Research (WRAIR) via the Geneva Foundation. After establishing “proof of concept” in the murine thigh infection model, the ultimate clinical applications will be in skin and soft tissue, and bone and joint infections. These are clear priorities for the Veterans Health Administration and the US Military.

产生金属-β-内酰胺酶 (MBL) 的革兰氏阴性病原体对我们的公共卫生构成重大威胁 因为针对具有这些耐药决定因素的细菌的治疗选择极其有限。 一般来说，MBL 是最令人担忧的碳青霉烯酶，它会灭活“最后手段”β-内酰胺类药物（例如亚胺培南） 和美罗培南）并抵抗所有市售β-内酰胺酶抑制剂（BLI）的主要挑战。 MBL 抑制剂的设计正在利用反应机制，因为它与 3 种不同的结构多样性有关 基于这种方法，我们联盟成功设计了一系列子类（B1、B2 和 B3）。 受非 β-内酰胺启发的创新化合物双噻唑烷 (BTZ) 和噻唑烷 (TZ) 迄今为止，BTZ 和 TZ 是独特的、有效的、非特异性的。 有毒的“跨类”MBL 抑制剂最近，我们确定了其抑制作用的结构基础，以及 它们的微生物活性（与碳青霉烯类药物结合使用时具有杀菌作用）。 BTZ 和 TZ 能够有效对抗产生 MBL 的革兰氏阴性细菌。 表现出类似的特性和效力，并且在某些情况下优于 BTZ。 该项目的总体奖励目标是在药物领域开展“高风险高”计划 发现开发一种有效的口服 MBL 抑制剂，该抑制剂可从胃肠道 (GI) 充分吸收 可以与口服碳青霉烯类药物替比培南匹酯 (Tbp-Pvx) 配合使用。 既定战略，增加 Pivoxil 集团，该集团在至少两个商业领域取得了成功 配方（头孢托仑匹酯和替比培南匹酯）并使其适应我们的开发化合物（BTZ） 由于丝氨酸碳青霉烯酶的肠外抑制剂已在临床使用（例如阿维巴坦， relebactam 和 vaborbactam），只有少数真正的 MBL 抑制剂正在开发中（QPX7728 和 taniborbactam），我们独特且特定的配方将解决未满足的医疗需求，即口服药物的需求 跨亚类 MBL 抑制剂 根据其成分的性质，Tbp-Pvx 也旨在保持稳定。 对抗超广谱 β-内酰胺酶 (ESBL) 和 C 类头孢菌素酶 (AmpC)， 此外，我们将缓解产生 MBL 的菌株中经常存在的耐药性决定因素。 与头孢菌素相关（抗性选择）作为先导化合物，我们已经鉴定出一种有效的 BTZ (L)。 syn CS319）与碳青霉烯类药物搭配使用时，可有效将 MIC 降低至易受影响的范围内。 作为替代方案，我们还合成了有效的 TZ 衍生物，我们建议开发第一种口服药物。 考虑开发碳青霉烯类和 MBL 抑制剂制剂，克服困难 治疗由 MBL 介导的碳青霉烯类耐药感染。 与阿根廷和乌拉圭的科学家建立伙伴关系，并将与 Wound 进行更密切的合作 沃尔特里德军感染科 (WID) 和实验治疗学 (ET) 部门 日内瓦基金会研究所 (WRAIR) 在小鼠身上建立了“概念验证”。 大腿感染模型，最终临床应用将在皮肤软组织、骨关节 这些是退伍军人健康管理局和美国军方明确的优先事项。