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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要近几十年来，细菌中抗生素耐药性的出现远远超过了新抗生素的发现速度。本研究的重点是抗生素有效性的合成和生物学研究。为此，林可酰胺已被确定为对这些现代病原体构成紧迫威胁的药物。自从克林霉素获批以来，尚未有新的林可酰胺类抗生素进入市场。 50 多年前（FDA，1970），对克林霉素的耐药性不断增强，并且有诱发生命的倾向。威胁性艰难梭菌（C. difficile）结肠炎由于其在当今医疗设备中的应用受到限制。此类天然产物结构复杂，半合成策略不足以支撑未来在该支架或相关支架内发现抗生素药物，将开发和开发有效的合成途径。实施以制备大量林可酰胺类似物，这是任何其他方法都无法获得的。包括主要候选物 iboxamycin 的类似物，其具有新型双环 oxepanoprolinamide 支架在体外和体内对多种多重耐药 (MDR) 细菌均有效。包括 MDR ESKAPE 病原体（屎肠球菌、金黄色葡萄球菌、肺炎克雷伯菌、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通过阐明体内抗生素开发的机制基础和驱动因素。伊博霉素和未来主要抗生素的功效，这项研究将为针对这些具有挑战性的病原体的临床前探索。