Structure-based microbially targeted prodrugs

基于结构的微生物靶向前药

• 批准号: 10509939
• 负责人: Cynthia Schieck Dowd
• 金额: $ 87.41万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10509939
• 关键词: 3-Dimensional; Anti-Bacterial Agents; Antibiotics; Bacteria; Biochemical; Biological; Biological Assay; Cefazolin; Centers for Disease Control and Prevention (U.S.); Chemical Models; Chemical Structure; Chemicals; Clinical; Crystallization; Development; Disease; Drug Kinetics; Ensure; Esters; Genus staphylococcus; Goals; Human; In Vitro; Infection; Intestinal Absorption; Kinetics; Knowledge; Label; Methicillin Resistance; Microbial Drug Resistance; Modification; Molecular; Monobactams; Mutagenesis; Nafcillin; Organism; Pathogenesis; Pathogenicity; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Planets; Prodrugs; Property; Proteins; Public Health; Publishing; Research; Resistance; Resolution; Serum; Site; Specificity; Staphylococcal Infections; Staphylococcus aureus; Structure; Structure-Activity Relationship; System; Therapeutic; analog; antimicrobial; antimicrobial drug; base; beta-Lactams; combat; design; drug development; drug discovery; esterase; esterase A; experience; improved; in vivo; inhibitor; iterative design; lipophilicity; methicillin resistant Staphylococcus aureus; microbial; novel; novel strategies; phosphonate; pre-clinical; structural biology; success; targeted agent; undecaprenyl pyrophosphate

PROJECT SUMMARY Antimicrobial drug resistance is an ongoing challenge for many serious diseases, including staphylococcal infections. Development of new antibiotics to combat methicillin-resistant Staphylococcus aureus—labeled a “serious threat” by the CDC—is a high priority. During drug development efforts, poor cellular penetration and drug-like features of compounds are a common roadblock. The studies in this proposal will advance a novel strategy to overcome this roadblock, by employing a prodrug approach, in which a bipartite molecule is activated intracellularly to release the active “warhead.” Central to our strategy is the determination of structure-activity relationships that define selective prodrug activation within S. aureus bacteria. We will advance this strategy by evaluating our preliminary prodrug SAR using two classes of inhibitors that are distinct in chemical structure and intracellular target. We will determine the enzymatic selectivity and evaluate how prodrugging alters biological properties of inhibitors, using in vitro and in vivo assays. In addition, we will use crystallographic approaches to delineate the structural features that define selective substrate recognition. Together, this project will establish and validate our approach for subsequent pre-clinical optimization of much-needed new antistaphylococcal therapies.

项目摘要 抗生素耐药性是许多严重疾病的持续挑战，包括 葡萄球菌感染开发新的抗生素以对抗甲氧西林耐药 被CDC列为“严重威胁”的金黄色葡萄球菌是一个高度优先事项。在药物 开发努力，差的细胞渗透性和化合物的药物样特征是常见的 路障该提案中的研究将提出一种新的战略来克服这一障碍， 使用前药方法，其中双链分子在细胞内被激活以释放药物。 主动弹头我们战略的核心是确定结构-活性关系， 定义S内的选择性前药活化。金黄色细菌。我们将通过评估来推进这一战略 我们初步的前药SAR使用两类化学结构不同的抑制剂， 胞内靶向。我们将确定酶的选择性，并评估前药如何改变 抑制剂的生物学特性，使用体外和体内测定。此外，我们将使用 晶体学方法来描绘定义选择性衬底的结构特征 识别.总之，该项目将建立和验证我们的方法，为后续的临床前 优化急需的新型抗葡萄球菌疗法。