Mechanisms and In Vivo Activity of a Next Generation Daptomycin Antibiotic

摘要 微生物对当前药物的耐药性正在上升，细菌的严重威胁正在变得越来越严重。 对所有药物免疫毫无疑问，重新关注抗感染化合物是非常重要的。 以防止传染病的潜在流行爆发。达托霉素是FDA批准的 用于治疗革兰氏阳性细菌感染的抗生素。它对钙有严格的要求，以满足其 抗菌活性最近的报告强调了不同菌株对达托霉素的耐药性。这推动 需要开发下一代达托霉素抗生素以避免耐药性。但 达托霉素化学结构的复杂性阻碍了通过传统的合成方法对这种抗生素进行修饰， 接近。我们最近报道了一种新的化学酶法合成特异性的 对达托霉素敏感和耐药细菌具有更强体外活性的达托霉素衍生物。的 与母体分子相反，新的类似物不需要钙来产生抗菌活性，这表明 新的作用机制。本提案的目标是研究新开发的 在体外和体内模型中的类似物。我们将使用多学科的方法，在化学和 生物学提供更多的深度机制和新产生的类似物的活动。具体目标1 将研究我们的达托霉素衍生物的理化和微观性质，以揭示 新合成化合物的机制。具体目标2将研究新的化学酶- 在动物模型中合成衍生物，以提供关于其体内活性和药代动力学的信息。 该提案强调转化研究，并将导致开发更强的抗生素， 规避阻力。因此，这项研究将对多种途径产生重大影响， 将这些化合物应用于临床。总的来说，该提案将为一项研究计划奠定基础， 整合了体内活性、微生物学、物理化学特性和机制见解，以获得新的 达托霉素生物多样性的途径。从这项研究中获得的结果将扩展到其他 脂肽类抗生素在它们的微生物抗性和活性方面的优势。这项研究将突出 化学酶促方法对于补充合成方法以修饰其他生物活性化合物的重要性。 这项提案也将与我的实验室的总体目标，以解决不断需要扩大化学 小分子的空间，以满足耐药微生物的日益增长的挑战，并提高其选择性。

Abstract Microbial resistance against current medications is on the rise, with the serious threat of bacteria becoming immune against all available drugs. There is no doubt that a renewed focus on anti-infective compounds is highly desired to prevent potential epidemic outbreaks of infectious diseases. Daptomycin is an FDA-approved antibiotic for the treatment of Gram-positive bacterial infections. It has a strict requirement for calcium to fulfill its antibiotic activity. Recent reports highlight the resistance of different strains against daptomycin. This urges the need for the development of next generation daptomycin antibiotics to circumvent resistance. However, the complexity of daptomycin’s chemical structure hinders modifying this antibiotic via traditional synthetic approaches. We have recently reported a novel chemoenzymatic method for the synthesis of specific daptomycin derivatives with stronger in vitro activity against daptomycin-susceptible and resistant bacteria. The new analogs, in contrast to the parent molecule, do not require calcium for antibacterial activity suggesting a new mechanism of action. The goal of this proposal is to study the new mechanism of the newly developed analogs in in vitro and in vivo models. We will use multidisciplinary approaches at the interface of chemistry and biology to provide more depth on the mechanisms and activity of the newly generated analogs. Specific Aim 1 will study the physicochemical and microscopic properties of our daptomycin derivatives to reveal the mechanisms of the newly synthesized compounds. Specific Aim 2 will study the new chemoenzymatically- synthesized derivatives in animal models to provide information on their in vivo activity and pharmacokinetics. This proposal emphasizes translational research and will lead to the development of stronger antibiotics that circumvent resistance. Hence this study will have a significant impact on multiple avenues that could lead to bridging these compounds to the clinic. Overall, the proposal will lay the groundwork for a research program that integrates in vivo activity, microbiology, physicochemical properties and mechanistic insights to access new routes to daptomycin biological diversity. The results obtained from this study will be extended to other lipopeptide antibiotics in terms of their microbial resistance and activity. This research will highlight the importance of chemoenzymatic approaches to complement synthetic ones to modify other bioactive compounds. This proposal will also align with my lab’s overall goal to address the constant need to expand the chemical space of small molecules to meet rising challenges of resistant microbes and improve their selectivity.