Oral Metallo-Beta-Lactamase Inhibitors: Exploiting Reaction Mechanisms

产金属β-内酰胺酶的革兰氏阴性菌是危害人类健康的重要病原菌 因为针对具有这些抗性决定子的细菌的治疗选择是极其有限的。在 通常，MBL是最令人担忧的碳青霉烯酶，使“最后手段”β-内酰胺失活（例如，亚胺培南 和美罗培南）并抵抗所有市售的β-内酰胺酶抑制剂（BLI）。的主要挑战 MBL抑制剂设计是利用反应机制，因为它涉及3种不同的结构多样性。 子类（B1、B2和B3）。基于这种方法，我们的联合体成功地设计了一系列 创新化合物，双噻唑烷（BTZ）和噻唑烷（TZs），灵感来自非β-内酰胺 用特定的金属结合基团修饰的“青霉素核心”。到目前为止，BTZ和TZs是独特的有效，非- 有毒的“交叉类”MBL抑制剂。最近，我们确定了它们抑制作用的结构基础， 它们的微生物活性（当与碳青霉烯组合时杀菌）。这激发了人们对 BTZ和TZs有效对抗产MBL革兰氏阴性菌的能力。有趣的是， 表现出类似的性质和效力，并且在某些情况下上级BTZ。 该项目的总体目标是着手实施一项“高风险-高回报”的禁毒计划。 发现开发一种有效的口服MBL抑制剂，可从胃肠道（GI）充分吸收 道，并可以与口服碳青霉烯类，tebipenem阿比西林（Tbp-Pvx）。我们正在挑选一个 建立战略，增加了一个阿西组，这已经成功地在至少两个商业 制剂（头孢托仑酯和替比培南酯），并使其适应我们开发的化合物（BTZ 和TZs）。由于丝氨酸碳青霉烯酶的肠胃外抑制剂已经在临床上使用（例如，阿维巴坦， 正处于开发中的有三种MBL抑制剂（曲马巴坦和戊硼巴坦），只有少数真正的MBL抑制剂（QPX 7728和QPX 7728）。 他尼博巴坦），我们独特和具体的制剂将解决未满足的医疗需求，即口服 交叉亚类MBL抑制剂。由于其组分的性质，Tbp-Pvx也旨在是稳定的 针对超广谱β-内酰胺酶（ESBLs）和C类头孢菌素酶（AmpCs）， 耐药决定簇通常存在于产MBL菌株中。此外，我们还将缓解 与头孢菌素相关（耐药选择）。作为先导化合物，我们已经确定了一个有效的BTZ（L syn CS319），当与碳青霉烯配对时，其有效地将MIC降低至易感范围内。作为 作为替代，我们还合成了有效的TZ衍生物。我们建议开发第一个口头 考虑开发碳青霉烯和MBL抑制剂制剂， 治疗MBL介导的碳青霉烯耐药感染。我们的实验评估来自于 与阿根廷和乌拉圭的科学家建立了伙伴关系，并将与Wound进行更密切的合作。 沃尔特里德陆军感染科和实验治疗学分支 研究所通过日内瓦基金会。在小鼠中建立了“概念验证”之后， 大腿感染模型，最终将在皮肤软组织、骨关节等临床应用 感染.这些都是退伍军人健康管理局和美国军方的明确优先事项。

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.