Development of a Dual-Targeting ClpP Activating Antibiotic

双靶点 ClpP 激活抗生素的开发

基本信息

批准号：
10760586
负责人：
Michael LaFleur
金额：
$ 100万
依托单位：
ARIETIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10760586
关键词：
Acute Antibiotic Resistance Antibiotic Therapy Antibiotics Antimicrobial Resistance Bacteremia Bacteria Cancer Etiology Cell Survival Cells Cessation of life Classification Clindamycin Clinical Coagulation Process Collaborations DNA-Directed RNA Polymerase Data Development Development Plans Dose Dose Fractionation Drug Kinetics Drug resistance Endocarditis Ensure Enterococcus Enterococcus faecalis Erythromycin Fiber Fibrin Foreign Bodies Future Genetic Transcription Genus staphylococcus Goals Growth Human Hybrids Implant In Vitro Infection Infective endocarditis Interphase Cell Investigational Drugs Lesion Medical Medicine Metabolic Microbial Biofilms Microbiology Modeling Mus Mycobacterium tuberculosis No-Observed-Adverse-Effect Level Patient Care Patients Peptide Hydrolases Periprosthetic joint infection Persons Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacology Phase Pneumonia Proteins Proteolysis RNA Rattus Repression Resistance Resistance development Rifampicin resistance Rifampin Rifamycins Route Safety Saint Jude Children&apos s Research Hospital Septicemia Streptococcus Streptococcus Group B Streptococcus pneumoniae Streptococcus pyogenes Structure Structure-Activity Relationship Testing Therapeutic Therapeutic Index Thigh structure Toxic effect Toxicokinetics Universities Vancomycin Vancomycin resistant enterococcus Vancomycin-resistant S. aureus Work World Health Organization analog antibiotic resistant infections antibiotic tolerance care costs clinical candidate clinical development combat design drug resistant bacteria efficacy study global health in vivo methicillin resistant Staphylococcus aureus mouse model pathogen pre-clinical prevent recurrent infection resistance frequency resistant strain safety study scale up single molecule subcutaneous success targeted treatment therapy development

项目摘要

The World Health Organization has declared that antimicrobial resistance is one of the biggest threats to global health. It was estimated that by 2050, deaths due to drug resistant bacteria will exceed those caused by cancer. The goal of this project is to develop a new ureadepsipeptide antibiotic (UDEP) to treat infections caused by Gram-positive pathogens, such as bacteremia, pneumonia, endocarditis, and prosthetic joint infections. UDEPs have a unique mechanism of action – they kill bacteria by causing cells to digest their own proteins. This mechanism enables activity against non-growing and dormant cells of bacteria that traditional antibiotics cannot kill. Thus, UDEPs have the potential to fill a large and unmet medical need for biofilm-related and difficult to treat infections. UDEP target what the CDC classifies as serious and concerning drug-resistant threats including Methicillin-Resistant Staphylococcus aureus (MRSA), Vancomycin-Resistant Enterococcus (VRE), Drug- Resistant Streptococcus pneumoniae, Vancomycin-Resistant Staphylococcus aureus, Erythromycin-Resistant Group A Streptococcus, and Clindamycin-Resistant Group B Streptococcus. The goal of this project is to determine if a new UDEP called 5192, which was specifically designed to have a low frequency of resistance, is a suitable candidate to enter investigational new drug enabling non-clinical development so it can be tested in human trials in the future.

世界卫生组织宣布抗菌素耐药性是全球面临的最大威胁之一据估计，到 2050 年，耐药细菌造成的死亡人数将超过癌症造成的死亡人数。该项目的目标是开发一种新的脲缩肽抗生素（UDEP）来治疗由以下疾病引起的感染：革兰氏阳性病原体，如菌血症、肺炎、心内膜炎和假体关节感染。它们具有独特的作用机制——它们通过使细胞消化自身的蛋白质来杀死细菌。该机制能够对抗细菌的非生长和休眠细胞，这是传统抗生素无法做到的因此，UDEP 有潜力满足与生物膜相关且难以治疗的大量未满足的医疗需求。 UDEP 针对 CDC 归类为严重且令人担忧的耐药威胁，包括耐甲氧西林金黄色葡萄球菌 (MRSA)、耐万古霉素肠球菌 (VRE)、药物- 耐药肺炎链球菌、耐药万古霉素金黄色葡萄球菌、耐药红霉素 A 组链球菌和耐克林霉素 B 组链球菌该项目的目标是。确定是否有名为 5192 的新 UDEP（专门设计为具有低频电阻）进入研究性新药的合适候选者，能够进行非临床开发，以便可以在未来的人体试验。