Discovery through chemical synthesis of antibiotics effective against modern bacterial pathogens

通过化学合成发现对现代细菌病原体有效的抗生素

• 批准号: 10419458
• 负责人: ANDREW G MYERS
• 金额: $ 76.67万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-10 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10419458
• 关键词: Acinetobacter baumannii; Address; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacteria; Binding; Biological; Carbohydrates; Chemistry; Clindamycin; Clinical; Clostridium difficile; Colitis; Collaborations; Collection; Crystallization; Cytochrome P450; Data; Development; Dose; ESKAPE pathogens; Enterobacter; Enterococcus faecium; Erythromycin; Evaluation; Feedback; Future; Glycosides; Hand; Human; Hydrogen Bonding; Hydrophobicity; In Vitro; Infection; Kinetics; Klebsiella pneumoniae; Label; Laboratories; Lead; Life; Literature; Liver Microsomes; Macrolides; Metabolic; Methods; Methylation; Methyltransferase; Modeling; Modern Medicine; Modernization; Modification; Molecular Conformation; Multi-Drug Resistance; Multiple Bacterial Drug Resistance; Natural Products; Pathway interactions; Pharmaceutical Chemistry; Preparation; Pseudomonas aeruginosa; Reporting; Research; Resistance; Ribosomal RNA; Ribosomes; Risk; Roentgen Rays; Route; Series; Site; Staphylococcus aureus; Structure; Sulfides; Sulfoxide; Testing; Thermodynamics; Tritium; analog; antibiotic design; base; chemical synthesis; combat; cost effective; design; drug discovery; efficacy study; emerging antibiotic resistance; experience; global health; improved; in vivo; innovation; insight; lead candidate; lincosamide; mouse model; multi-drug resistant pathogen; novel; novel strategies; oxidation; pathogen; pathogenic bacteria; pre-clinical; programs; resistance gene; scaffold; small molecule; sugar; weapons

PROJECT SUMMARY/ABSTRACT In recent decades, the emergence of antibiotic resistance in bacteria has greatly outpaced the discovery of novel antibacterial agents. This research is focused on the synthesis and biological study of antibiotics effective against these modern pathogens of urgent threat. To this end, the lincosamides have been identified as an underexploited class of antibiotics. No new lincosamide has entered the market since clindamycin was approved more than 50 years ago (FDA, 1970). Growing resistance to clindamycin and its propensity to induce life- threatening Clostridioides difficile (C. difficile) colitis have limited its utility in today’s armamentarium. Due to the structural complexity of this class of natural products, semi-synthetic strategies are insufficient to support future antibiotic drug discovery within this or related scaffolds. Here, efficient synthetic pathways will be developed and implemented to prepare a large collection of lincosamide analogs inaccessible by any other means. These include analogs of a lead candidate, iboxamycin, which features a novel bicyclic oxepanoprolinamide scaffold and is efficacious in vitro and in vivo against a broad range of multi-drug resistant (MDR) bacteria. The latter include MDR ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.), identified by the WHO as targets of highest priority in antibiotic development. By elucidating the mechanistic underpinnings and drivers of in vivo efficacy of iboxamycin and future lead antibiotics, this research will deliver multiple novel antibiotic scaffolds for preclinical exploration to target these challenging pathogens.

项目摘要/摘要 近几十年来，细菌中抗生素耐药性的出现大大超过了新抗生素的发现。 抗菌剂本研究的重点是有效抗真菌抗生素的合成和生物学研究。 这些现代病原体的紧迫威胁。为此，林可酰胺已被鉴定为 开发不足的一类抗生素自克林霉素获批以来，没有新的林可酰胺进入市场 50多年前（FDA，1970）。对克林霉素的耐药性及其诱发生命的倾向- 威胁性艰难梭菌（Clostridioides difficile，C. difficile）结肠炎限制了其在当今医疗设备中的效用。由于 由于这类天然产物结构复杂，半合成策略不足以支持未来的发展。 在这个或相关的支架中发现抗生素药物。在这里，将开发有效的合成途径， 实施本发明以制备任何其他手段都无法获得的大量林可酰胺类似物。这些 包括先导候选物iboxamycin类似物，其特征在于新的双环氧杂环庚脯氨酰胺骨架 并且在体外和体内对广泛的多药耐药（MDR）细菌有效。后者 包括MDR ESKAPE病原体（屎肠球菌，金黄色葡萄球菌，肺炎克雷伯氏菌， 鲍曼不动杆菌、铜绿假单胞菌和肠杆菌属），被世界卫生组织确定为目标 抗生素开发的最高优先级。通过阐明在体内的机制基础和驱动程序， iboxamycin和未来主要抗生素的功效，这项研究将提供多种新型抗生素支架， 针对这些具有挑战性的病原体进行临床前探索。