Development of a Dual-Targeting ClpP Activating Antibiotic

双靶点 ClpP 激活抗生素的开发

• 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
• 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' 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

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最大的威胁之一， 健康据估计，到2050年，耐药细菌导致的死亡人数将超过癌症。 该项目的目标是开发一种新的脲缩肽抗生素（UDEP），用于治疗由以下原因引起的感染： 革兰氏阳性病原体，如菌血症、肺炎、心内膜炎和人工关节感染。UDEP 它们有一种独特的作用机制--它们通过使细胞消化自身的蛋白质来杀死细菌。这 这种机制能够对传统抗生素无法对抗的非生长和休眠细菌细胞发挥作用 杀人因此，UDEP有潜力填补生物膜相关和难以治疗的大量未满足的医疗需求 感染. UDEP针对疾病预防控制中心归类为严重和有关耐药威胁的目标，包括 耐甲氧西林金黄色葡萄球菌（MRSA）、耐万古霉素肠球菌（VRE）、耐药 耐药肺炎链球菌、耐万古霉素金黄色葡萄球菌、耐红霉素 A组链球菌和克林霉素耐药B组链球菌。该项目的目标是 确定是否有一个新的UDEP称为5192，这是专门设计的，有一个低频率的阻力，是 一个合适的候选药物进入研究新药，使非临床开发，使其可以在 未来的人体试验