Novel oxadiazols for the treatment of drug-resistant gram-positive bacteria

用于治疗耐药革兰氏阳性菌的新型恶二唑类药物

• 批准号: 7988818
• 负责人: Mayland F Chang
• 金额: $ 106.96万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7988818
• 关键词: Accounting; Anti-Bacterial Agents; Antibiotics; Bacteremia; Bacterial Infections; Binding; Binding Sites; Biological Availability; Cell Wall; Cessation of life; Clinic; Complex; Computer Simulation; Development; Docking; Dose; Drug Interactions; Drug Kinetics; Drug or chemical Tissue Distribution; Drug resistance; Electronics; Enterococcus; Enzymes; Evaluation; Excretory function; Genome; Goals; Gold; Gram-Positive Bacteria; Grant; Hand; Hospitalization; Housing; In Vitro; Infection; Investigation; Laboratories; Lead; Letters; Licensing; Light; Linezolid; Medical; Metabolic; Metabolism; Methods; Modeling; Molecular; Mus; Nature; Nosocomial Infections; Organism; Penicillin-Binding Proteins; Pharmaceutical Preparations; Pharmacologic Substance; Photoaffinity Labels; Positioning Attribute; Property; Proteins; Proteome; Resistance; Resort; Rodent; Rodent Model; Safety; Screening procedure; Skin; Soft Tissue Infections; Solubility; Staging; Staphylococcus aureus; Structure; Surgical Wound Infection; Therapeutic Index; Toxic effect; Urinary tract infection; Validation; Vancomycin; Vancomycin Resistance; Vancomycin resistant enterococcus; Virtual Library; Water; Work; absorption; base; combat; combinatorial; commercialization; drug candidate; drug resistant bacteria; human disease; in vivo; methicillin resistant Staphylococcus aureus; novel; pre-clinical; programs; resistance mechanism

DESCRIPTION (provided by applicant): Staphylococcus aureus is responsible for a number of human diseases, including skin and soft tissue infections. Annually, 292,000 hospitalizations in the US are due to S. aureus infections, of which 126,000 are related to methicillin-resistant Staphylococcus aureus (MRSA), resulting in 19,000 deaths. Enterococci are the leading cause of nosocomial bacteremia, surgical wound infections, and urinary tract infections. Vancomycin-resistant enterococci (VRE) accounts for >25% of the enterococci hospital-acquired infections in the US. A novel structural lead, the oxadiazol class of antibiotics, has emerged from our work. The oxadiazol antibiotics show high in vitro potency against Gram-positive bacteria comparable to those of linezolid and superior to vancomycin (both considered gold standards) and show in vivo activity. In addition, the oxadiazols have activity against vancomycin- resistant MRSA and VRE, two organisms for which treatment options are extremely limited. The compounds in hand at this point are not highly water soluble and their pharmacokinetic properties are not optimized. This project proposes to optimize the initial lead discovery to come up with lead candidates with the correct mix of pharmacological activity, PK attributes, and safety profile, such that an oxadiazol drug candidate will be selected and advanced to preclinical development. We also propose a novel method for the identification and validation of the target(s) for the oxadiazol antibiotics in the proteome of S. aureus and put forth a whole genome method for investigation of the mechanism of resistance to this class of antibiotics. Infections caused by drug-resistant bacteria are an increasing unmet medical need. The drug of last resort, linezolid, is reserved for use in hard-to-treat methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE). New treatments are urgently needed to combat the emergence of resistance to any antibiotic after introduction of the antibiotic to the clinic. Our group has developed a new oxadiazol class of antibiotics that shows activity against vancomycin-resistant MRSA and VRE comparable to linezolid. Our goal is to develop a new class of antibiotics to treat drug-resistant bacterial infections.

描述（由申请人提供）：金黄色葡萄球菌可引起多种人类疾病，包括皮肤和软组织感染。美国每年有 292,000 例因金黄色葡萄球菌感染住院，其中 126,000 例与耐甲氧西林金黄色葡萄球菌 (MRSA) 有关，导致 19,000 人死亡。肠球菌是院内菌血症、手术伤口感染和尿路感染的主要原因。在美国，耐万古霉素肠球菌 (VRE) 占医院获得性肠球菌感染的 25% 以上。我们的工作中出现了一种新的结构先导，即恶二唑类抗生素。恶二唑类抗生素在体外对革兰氏阳性菌表现出较高的效力，与利奈唑胺相当，优于万古霉素（均被认为是金标准），并显示出体内活性。此外，恶二唑还具有对抗万古霉素耐药性 MRSA 和 VRE 的活性，这两种生物的治疗选择极为有限。目前手中的化合物水溶性不高，并且其药代动力学特性尚未优化。该项目建议优化最初的先导化合物发现，以提出具有药理活性、PK 属性和安全性特征的正确组合的先导候选药物，从而选择恶二唑候选药物并推进临床前开发。我们还提出了一种新方法，用于鉴定和验证金黄色葡萄球菌蛋白质组中恶二唑类抗生素的靶点，并提出了用于研究此类抗生素耐药机制的全基因组方法。 耐药细菌引起的感染日益成为未得到满足的医疗需求。最后的药物利奈唑胺被保留用于治疗难以治疗的耐甲氧西林金黄色葡萄球菌（MRSA）和耐万古霉素肠球菌（VRE）。抗生素引入临床后，迫切需要新的治疗方法来对抗抗生素耐药性的出现。我们的团队开发了一种新的恶二唑类抗生素，其对抗万古霉素耐药性 MRSA 和 VRE 的活性与利奈唑胺相当。我们的目标是开发一类新型抗生素来治疗耐药细菌感染。