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.

此SBIR期IIB提案的目的是开发一种适合 口服给药可安全有效地治疗受甲氧西林可破坏感染的患者 和抗性金黄色葡萄球菌和表皮葡萄球菌（MSSA，MRSA，MSSE和MRSE）。 MRSA MRSE是医院和社区中血液感染的主要原因，并且正在上升 阿片类药物危机日益增长的静脉注射药物使用。确实，MRSA仍然是 在美国，耐药细菌病原体的死亡率。治疗通常依靠万古霉素（van）， daptomycin（DAP）或黄唑烷酮，例如linezolid（LZD）和Tedizolid（TZD），但所有这些药物均具有 局限性，包括仅IV剂货车和DAP给药，lzd＆tzd的毒性也很长时间 随着对所有人的抵抗力增长。相反，β-内酰胺抗生素历史上具有最大的影响 曾经治疗细菌感染的抗生素类 MRSA/E。重建β-内酰胺作为革兰氏阳性细菌感染的护理疗法的标准 MRSA/E将为临床医生提供一种新的治疗选择，并可以改善抗生素 管理对DAP和LZD的抵抗力的管理。根据先前的SBIR快速轨道赠款（R44AI136213）， 我们发现并开发了一种称为tarocins的新型化合物，它们有选择地抑制非 - 葡萄球菌中的必需酶芋头，WTA的耗竭将MRSA和MRSE重新敏感至裂解 β-内酰胺抗生素的作用。这表明tarocin与合适的lactam的结合将 根据安全熟悉的药物类提供有用的MRSA/E疗法。以我们以前的工作为基础 由于该提案成功完成目标而导致的可交付能力是机械上的 具有细菌活性有效的新型，安全且有效的PO给药的塔洛蛋白/-lactam组合剂 针对包括MRSA和MRSE在内的MDR葡萄球菌，上演了辅助研究。 我们对该提案的目标是： AIM1。PCC选择适用于PO给药的turoc素潜力。 目标2。ta aro素PCC的扩展和配方。 目标3。选择最佳β-内酰胺伴侣。 AIM 4。使用塔洛蛋白PCC/最佳β-内酰胺伴侣组合的功效研究。 AIM 5。在大鼠和tarocin PCC的大鼠和狗中的安全性，代谢，PK和非GLP毒理学。