Oral Metallo-Beta-Lactamase Inhibitors: Exploiting Reaction Mechanisms

产生金属β-内酰胺酶的革兰氏阴性病原菌MBLS严重威胁着我们的公共健康 由于针对拥有这些耐药决定因素的细菌的治疗选择极其有限。在……里面 一般说来，MBL是最令人担忧的碳青霉烯酶，它会使β-内酰胺类抗生素(例如亚胺培南)失活 和美罗培南)，并抵抗所有商用的β-内酰胺酶抑制剂(BLI)。面临的主要挑战 MBL抑制剂的设计正在利用反应机理，因为它与三个不同的结构多样性有关 子类(B1、B2和B3)。基于这种方法，我们联合体成功地设计了一系列 创新的化合物，双噻唑烷(BTZ)和噻唑烷(TZS)，灵感来自非β-内酰胺 “青霉素芯”装饰有特定的金属结合基团。到目前为止，BTZ和TZS是唯一有效的、非 有毒的“跨类”MBL抑制剂。最近，我们确定了它们抑制作用的结构基础，并且 它们的微生物活性(与碳青霉烯类结合时具有杀菌作用)。这激发了人们对 BTZ和TZS对产MBL革兰氏阴性菌的抗菌能力有趣的是，新奇的TZS 表现出类似的性质和效力，在某些情况下优于BTZ。 这个项目的首要目标是在毒品领域开始一个“高风险-高回报”的计划。 发现一种能从胃肠道充分吸收的有效口服MBL抑制剂(GI) 经肠道，可与口服碳青霉烯，替比培南枢轴(TBP-PVX)合作。我们正在增选一名 既定的战略，增加了Pivoxil集团，这至少在两个商业领域取得了成功 剂型(头孢妥仑和替比培南)并使其适应我们的开发化合物(BTZ) 和TZS)。由于用于丝氨酸碳青霉烯酶的非肠外抑制剂已经在临床上使用(例如，阿维巴坦， 释放巴坦和瓦博巴坦)，只有少数真正的MBL抑制剂正在开发中(QPX7728和 塔尼博巴坦)，我们独特而具体的配方将解决未得到满足的医疗需求，即口腔 交叉亚类MBL抑制剂。由于其组件的性质，TBP-PVX也旨在保持稳定 抗超广谱β-内酰胺酶(ESBLS)和C类头孢菌素酶(AmpCs)，这两种酶是 耐药决定因素通常存在于产MBL菌株中。此外，我们将缓解这些问题 与头孢菌素相关(耐药选择)。作为一种先导化合物，我们已经确定了一种有效的BTZ(L SYN CS319)，当与碳青霉烯类药物配伍时，可有效地将MIC降低到敏感范围内。作为一种 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腔 可考虑开发攻克难的碳青霉烯类和MBL抑制剂配方 治疗MBLS介导的碳青霉烯类耐药感染。我们的实验评估源于CLOSE 与阿根廷和乌拉圭的科学家合作，并将与伤口进行更密切的合作 沃尔特里德军感染科(WID)和实验治疗学(ET)分部 研究所(WRAIR)通过日内瓦基金会。在小鼠体内建立“概念证明”之后 大腿感染模型的最终临床应用将在皮肤和软组织，以及骨和关节 感染。这些都是退伍军人健康管理局和美国军方明确的优先事项。

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.