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 SBIR IIB 期提案的目标是开发一种新型 tarocin/-内酰胺组合剂，适用于 口服给药可安全有效地治疗甲氧西林敏感菌感染患者 以及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 是医院和社区血流感染的主要原因，并且在 日益严重的阿片类药物危机加剧了静脉注射毒品的使用。事实上，MRSA 仍然是导致感染的第二大原因。 美国耐药细菌病原体造成的死亡率。治疗通常依靠万古霉素（VAN）， 达托霉素 (DAP) 或恶唑烷酮类药物，例如利奈唑胺 (LZD) 和特地唑胺 (TZD)，但所有这些药物都具有 局限性，包括 VAN 和 DAP 仅静脉注射、LZD 和 TZD 长期使用的毒性，以及 随着对所有人的抵制不断增长。相反，β-内酰胺类抗生素历来在所有抗生素中影响最大。 一类抗生素曾经用于治疗细菌感染，但它们的功效已因细菌感染的出现而受到削弱。 MRSA/E。重新建立 β-内酰胺作为革兰氏阳性细菌感染的护理治疗标准，包括 MRSA/E 将为临床医生提供新的治疗选择，并改进抗生素 减轻对 DAP 和 LZD 的抵抗力的管理。根据先前的 SBIR 快速通道拨款 (R44AI136213)， 我们发现并开发了一类名为 tarocins 的新型化合物，它可以选择性地抑制非 Staph 中必需的酶 TarO，由此导致的 WTA 消耗使 MRSA 和 MRSE 对裂解物重新敏感 β-内酰胺类抗生素的作用。这表明塔罗辛与合适的 β-内酰胺的组合将 基于安全且熟悉的药物类别，为 MRSA/E 提供有用的治疗方法。在我们之前的工作的基础上， 成功完成本提案中的目标所产生的可交付成果将是 新颖、安全、有效的 PO 给药塔罗星/β-内酰胺组合剂，具有有效的杀菌活性 针对 MDR 葡萄球菌（包括 MRSA 和 MRSE）的药物，已进入 IND 启用研究。 我们此提案的目标是： 目的 1. PCC 选择适合 PO 给药的 tarocin 增效剂。 目标 2. tarocin PCC 的放大和配制。 目标 3. 选择最佳 β-内酰胺伴侣。 目标 4. 使用 tarocin PCC/最佳 β-内酰胺伴侣组合进行功效研究。 目标 5. tarocin PCC 在大鼠和狗中的安全性、代谢、PK 和非 GLP 毒理学。