Mechanisms and In Vivo Activity of a Next Generation Daptomycin Antibiotic

下一代达托霉素抗生素的机制和体内活性

• 批准号: 10593558
• 负责人: Sherif I Elshahawi
• 金额: $ 6.9万
• 依托单位: CHAPMAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-04 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10593558
• 关键词: Address; Amino Acids; Animal Model; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotic Therapy; Antibiotics; Bacteremia; Bacteria; Biodiversity; Biological Assay; Biology; Calcium; Cell Wall; Chemical Structure; Chemicals; Chemistry; Clinic; Combating Antibiotic Resistant Bacteria; Communicable Diseases; Complement; Daptomycin; Development; Diphosphates; Disease Outbreaks; Dose; Drug Kinetics; Endocarditis; Enterococcus faecalis; FDA approved; Face; Fluorescence Spectroscopy; Funding Opportunities; Future; Generations; Goals; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Hand; Hot Spot; Immune; In Vitro; Infection; Lead; Membrane Lipids; Methodology; Methods; Microbe; Microbiology; Microscopic; Microscopy; Modeling; Modification; Molecular Conformation; Multi-Drug Resistance; Mus; NMR Spectroscopy; Parents; Pathogenicity; Patients; Peptides; Periodicity; Pharmaceutical Preparations; Predisposition; Process; Property; Proteins; Publishing; Reporting; Research; Resistance; Resistance development; Route; Running; Skin; Staphylococcus aureus; Statistical Data Interpretation; Structure; Systemic infection; Thigh structure; Toxic effect; Training; Translational Research; Uncertainty; analog; antimicrobial; assay development; bacterial resistance; cytotoxicity; epidemic potential; experimental study; global health; improved; in vitro Assay; in vitro activity; in vivo; in vivo Model; innovation; insight; interdisciplinary approach; microbial; microorganism; mortality; next generation; novel; prevent; programs; public health relevance; resistant strain; small molecule

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.

抽象的 微生物对当前药物的耐药性正在上升，细菌的严重威胁变得 免疫所有可用药物。毫无疑问，对抗感染化合物的重新关注很高 希望防止传染病的潜在流行病暴发。 Daptomycin是FDA批准的 用于治疗革兰氏阳性细菌感染的抗生素。它严格要求钙实现其 抗生素活性。最近的报道突出了不同菌株对达霉素的抗性。这敦促 需要开发下一代Daptomycin抗生素以规避耐药性。但是， Daptomycin化学结构的复杂性阻碍了通过传统合成的修饰这种抗生素 方法。我们最近报道了一种合成特异性的新型化学酶方法 daptomycin衍生物具有较强的体外活性，可对daptomycin subsuptection和抗性细菌。 与母体分子相比，新的类似物不需要钙的抗菌活性表明 新的作用机制。该提案的目的是研究新开发的新机制 体外和体内模型中的类似物。我们将在化学界面上使用多学科方法， 生物学可以更深入地了解新生成的类似物的机制和活性。具体目标1 将研究我们的daptomycin衍生物的物理和微观特性，以揭示 新合成化合物的机制。特定的目标2将研究新的化学酶 - 在动物模型中合成的衍生物，以提供有关其体内活性和药代动力学的信息。 该提议强调转化研究，并将导致更强大的抗生素的发展 绕过阻力。因此，这项研究将对可能导致的多种途径产生重大影响 将这些化合物桥接到诊所。总体而言，该提案将为研究计划奠定基础 整合体内活动，微生物学，物理特性和机械见解以访问新的 Daptomycin生物学多样性的路线。从这项研究中获得的结果将扩展到其他 脂肽抗生素在其微生物耐药性和活性方面。这项研究将突出显示 化学酶方法补充合成方法以修饰其他生物活性化合物的重要性。 该建议还将与我的实验室的总体目标保持一致，以解决扩展化学物质的不断需求 小分子的空间满足抗性微生物的挑战并提高其选择性。