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.

SBIR IIB期提案的目标是开发一种新的tarocin/-内酰胺联合药物，适用于