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: 10547079
• 负责人: Terry Roemer
• 金额: $ 99.94万
• 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/10547079
• 关键词: Affect; Anabolism; Antibiotics; Award; Bacterial Infections; Binding Proteins; 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; Microbiology; Modeling; Molecular; Monobactams; Mus; Names; No-Observed-Adverse-Effect Level; Oral; Oral Administration; Oxazolidinones; Pathway interactions; Patients; Pattern; Penicillin-Binding Proteins; Pharmaceutical Preparations; Pharmacodynamics; Phase; Plasma Proteins; 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; base; beta-Lactams; candidate selection; clinical toxicology; comparative efficacy; efficacy study; improved; in vivo; indexing; methicillin resistant Staphylococcus aureus; mortality; novel; novel therapeutics; opioid epidemic; pathogenic bacteria; pre-clinical; 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塔罗辛/β-内酰胺组合药物， 口服给药，可用于安全有效地治疗甲氧西林敏感性 和耐药金黄色葡萄球菌和表皮葡萄球菌（MSSA、MRSA、MSSE和MRSE）。MRSA 和MRSE是医院和社区血液感染的主要原因， 越来越多的阿片类药物危机助长了静脉注射毒品的使用。事实上，MRSA仍然是导致 美国耐药细菌病原体的死亡率。常规治疗依赖于万古霉素（货车）， 达托霉素（DAP）或恶唑烷酮如利奈唑胺（LZD）和替地唑胺（TZD），但所有这些药剂都具有 局限性，包括货车和DAP仅IV给药，LZD和TZD长期使用的毒性，以及 对所有人的抵抗力越来越强相反，β-内酰胺类抗生素在历史上具有最大的影响， 这类抗生素曾经用于治疗细菌感染，但它们的功效已被 MRSA/E.重新确立β-内酰胺类药物作为革兰氏阳性细菌感染的标准治疗，包括 MRSA/E将为临床医生提供一种新的治疗选择， 管理以减轻对DAP和LZD的耐药性。根据先前的SBIR快速通道赠款（R44 AI 136213）， 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- 葡萄球菌中的必需酶TarO，以及由此产生的WTA的消耗使MRSA和MRSE对溶解性 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 基于安全和熟悉的药物类别为MRSA/E提供有用的治疗。在我们以前工作的基础上， 成功完成本建议书中的目标所产生的交付成果将是一个机制性的 具有杀菌活性的新型、安全和有效的口服给药塔罗辛/β-内酰胺组合药剂 包括MRSA和MRSE在内的MDR葡萄球菌，分期进入IND使能研究。 我们提出这项建议的目的是： 目标1. PCC选择适合于PO施用的塔罗辛增效剂。 目标2.塔罗辛PCC的规模放大和制剂。 目标3.最佳β-内酰胺伴侣的选择。 目标4。使用塔罗辛PCC/最佳β-内酰胺伴侣组合的功效研究。 目标5。Tarocin PCC在大鼠和犬中的安全性、代谢、PK和非GLP毒理学。