Development of a PO-administered beta-lactam-tarocin combination agent to treat methicillin susceptible and methicillin resistant Staphylococci

开发用于治疗甲氧西林敏感和甲氧西林耐药葡萄球菌的 PO 给药 β-内酰胺-塔罗辛组合药物

• 批准号: 10662488
• 负责人: Terry Roemer
• 金额: $ 99.11万
• 依托单位: PROKARYOTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-05 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662488
• 关键词: Affect; Anabolism; Antibiotics; Award; Bacterial Infections; Binding Proteins; Biological; Biological Availability; Canis familiaris; Chemosensitization; Clinical; Colony-forming units; Communities; Daptomycin; Data; Development; Dose; Drug Interactions; Drug Kinetics; Drug resistance; Drug usage; Effectiveness; Enzyme Inhibitor Drugs; Enzymes; Formulation; Fractionation; Genes; Genus staphylococcus; Goals; Gram-Positive Bacterial Infections; Grant; Hemolysis; HepG2; Hepatocyte; Hospitals; Human; In Vitro; Infection; International; Intestines; Lactams; Lead; Linezolid; Liquid substance; Lytic; Mediating; Metabolic; Metabolism; Methicillin; Methicillin Resistance; Modeling; Molecular; Mus; Names; No-Observed-Adverse-Effect Level; Oral; Oral Administration; Oxazolidinones; Pathway interactions; Patients; Pattern; Penicillin-Binding Proteins; Pharmaceutical Preparations; Pharmacodynamics; Phase; Plasma Proteins; Predisposition; Property; Rattus; Regimen; Reporting; Resistance; Risk; Safety; Sepsis; Small Business Innovation Research Grant; Solubility; Staphylococcal Infections; Staphylococcus aureus; Staphylococcus epidermidis; Taro Vegetable; Teichoic Acids; Testing; Therapeutic Index; Thigh structure; Toxic effect; Toxicology; United States; Vancomycin; Work; analog; bactericide; beta-Lactams; candidate selection; comparative efficacy; efficacy study; improved; in vivo; indexing; methicillin resistant Staphylococcus aureus; mortality; novel; novel therapeutics; opioid epidemic; pathogenic bacteria; pre-clinical; pre-clinical assessment; programs; resistance frequency; scale up; standard of care; synergism

The goal of this SBIR Phase IIB proposal is to develop a novel tarocin/-lactam combination agent suitable for oral administration which could be used to safely and effectively treat patients infected by methicillin-susceptible and resistant Staphylococcus aureus & Staphylococcus epidermidis (MSSA, MRSA, MSSE & MRSE). MRSA and MRSE are a major cause of bloodstream infections in the hospital and in the community, and are rising on account of IV drug use fueled by the growing opioid crisis. Indeed, MRSA remains the second leading cause of mortality by drug-resistant bacterial pathogens in the USA. Treatment routinely relies on vancomycin (VAN), daptomycin (DAP), or oxazolidinones such as linezolid (LZD) and tedizolid (TZD), but all of these agents have limitations, including IV-only administration for VAN & DAP, toxicities with prolonged use for LZD & TZD, as well as growing resistance to all. Conversely, β-lactam antibiotics have historically had the greatest impact of any class of antibiotics ever to treat bacterial infections, but their efficacy has been eroded by the emergence of MRSA/E. Reestablishing β-lactams as a standard of care therapy for Gram-positive bacterial infections including MRSA/E would provide clinicians with a new therapeutic option and would allow for improved antibiotic stewardship to mitigate resistance to DAP and LZD. Under a preceding SBIR fast-track grant (R44AI136213), we have discovered and developed a novel class of compounds called tarocins, which selectively inhibit the non- essential enzyme TarO in Staph, and the resulting depletion of WTA re-sensitizes MRSA and MRSE to the lytic effects of β-lactam antibiotics. This suggests that the combination of a tarocin with a suitable -lactam would furnish a useful therapy for MRSA/E based on a safe and familiar drug class. Building on our previous work, the deliverable resulting from the successful completion of the aims in this proposal would be a mechanistically novel, safe, and effective PO administered tarocin/-lactam combination agent with bactericidal activity effective against MDR staphylococci, including MRSA and MRSE, staged to enter IND-enabling studies. Our aims for this proposal are: Aim 1. PCC selection of tarocin potentiator suitable for PO administration. Aim 2. Scale-up and Formulation of tarocin PCC. Aim 3. Selection of optimum β-lactam partner. Aim 4. Efficacy studies using tarocin PCC/optimum β-lactam partner combination. Aim 5. Safety, Metabolism, PK, and non-GLP Toxicology in rat and dog of the tarocin PCC.

该方案的目标是开发一种新型的酒石素/-内酰胺复合剂，适用于 可用于安全有效地治疗甲氧西林敏感患者感染的口服给药 耐药金黄色葡萄球菌和表皮葡萄球菌(MSSA、MRSA、MSSE和MRSE)。耐甲氧西林金黄色葡萄球菌 和MRSE是医院和社区血液感染的主要原因，并且正在上升 对日益严重的阿片类药物危机加剧的静脉注射药物使用的解释。事实上，耐甲氧西林金黄色葡萄球菌仍然是导致 美国耐药细菌病原体的死亡率。常规治疗依赖万古霉素(VAN)， 达托霉素(DAP)或恶唑烷酮类药物，如利奈唑胺(LZD)和替氮唑胺(TZD)，但所有这些药物都有 限制，包括仅静脉注射VAN和DAP，以及长期使用LZD和TZD的毒性 因为对所有人的抵抗力都在增强。相反，历史上β-内酰胺类抗生素的影响是所有 曾经用于治疗细菌感染的一类抗生素，但其效力已被 重新建立β-内酰胺类药物作为治疗革兰氏阳性细菌感染的标准护理疗法，包括 MRSA/E将为临床医生提供一种新的治疗选择，并将允许改进抗生素 减少对DAP和LZD的抵抗的管理。在先前的SBIR快速通道授权(R44AI136213)下， 我们已经发现并开发了一类新的化合物，称为Tarocins，它选择性地抑制非 金黄色葡萄球菌中的关键酶Taro，以及由此导致的WTA耗竭使MRSA和MRSE对裂解酶重新敏感 β-内酰胺类抗生素的疗效观察。这表明，酒石素与合适的-内酰胺的组合将 基于安全和熟悉的药物类别，为MRSA/E提供有用的治疗方法。在我们以前工作的基础上， 成功完成本提案中的目标所产生的可交付成果将是一个机械性的 新型、安全、有效的PO给药的有效杀菌活性的-内酰胺类组合制剂 针对耐多药葡萄球菌，包括耐甲氧西林金黄色葡萄球菌和耐甲氧西林金黄色葡萄球菌，进入IND使能研究。 我们提出这项建议的目的是： 目的1.PCC筛选出适合PO给药的蒿甲素增效剂。 目的2.芋红素聚乙醇胺的放大及制备。 目的3.最佳β-内酰胺配对的筛选。 目的4.蒲公英/β-内酰胺最佳配对方案的疗效研究。 目的5.蒲公英胶囊的安全性、代谢、PK和非GLP毒理学研究。