Development of MRS-2541, a methionyl-tRNA synthetase inhibitor, for Gram positive bacterial infections.

开发 MRS-2541，一种甲硫氨酰-tRNA 合成酶抑制剂，用于治疗革兰氏阳性细菌感染。

• 批准号: 10699105
• 负责人: Elke Lipka
• 金额: $ 99.85万
• 依托单位: TSRL, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-03 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10699105
• 关键词: Accident and Emergency department; Acute; Address; Anaerobic Bacteria; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacteremia; Bacteria; Bacterial Antibiotic Resistance; Bacterial Drug Resistance; Bacterial Infections; Bacterial Proteins; Biological Availability; Characteristics; Chemistry; Chronic Obstructive Pulmonary Disease; Clinical; Cytochrome P450; Cytochromes; Data; Development; Diabetes Mellitus; Dose; Drug Interactions; Drug resistance; Drug usage; Enrollment; Ensure; Enterococcus faecium; Enzymes; Exposure to; Fluoroquinolones; Formulation; Foundations; Goals; Gram-Positive Bacterial Infections; Grant; Growth; Health care facility; Healthcare Systems; Hospitalization; Hospitals; Human; Hypersensitivity; In Vitro; Incidence; Individual; Infection; Intermediate resistance; Intravenous; Investigational Drugs; Investigational New Drug Application; Kidney Failure; Kilogram; Laboratory Research; Lead; Linezolid; Macrophage; Mammalian Cell; Medical; Metabolic; Methionine-tRNA Ligase; Methodology; Microbiology; Minimum Inhibitory Concentration measurement; Mitochondria; Modeling; Mus; Oral; Oral Administration; Organism; Oxazolidinones; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Phase; Preclinical Drug Development; Program Development; Protein Biosynthesis; Public Health; Rattus; Reaction; Regimen; Research; Resistance; Risk; Risk Factors; Rodent; Route; Safety; Selective Serotonin Reuptake Inhibitor; Skin; Small Business Innovation Research Grant; Staphylococcal Infections; Staphylococcus aureus; Streptococcal Infections; Streptococcus; Streptococcus pyogenes; Structure; Testing; Tetracyclines; Therapeutic; Thigh structure; Toxic effect; Toxicology; United States; Universities; Vancomycin; Vancomycin resistant enterococcus; Vancomycin-resistant S. aureus; Visit; Washington; aging population; beta-Lactams; comparative efficacy; cytotoxicity; dalbavancin; design; efficacy outcomes; exposed human population; improved; in vivo; in vivo evaluation; inhibitor; lead candidate; member; methicillin resistant Staphylococcus aureus; mortality; mouse model; new chemical entity; novel; novel antibiotic class; novel therapeutics; oritavancin; pathogen; pharmacokinetics and pharmacodynamics; pleuromutilin; pre-clinical research; preclinical development; product development; programs; recurrent infection; research and development; resistance frequency; resistance mechanism; safety study; scale up; skills; small molecule; subcutaneous; systems research

The objective of this grant is the preclinical development of MRS-2541, a novel antibiotic structure targeting Gram+ bacteria by a new mechanism of action. MRS-2541 inhibits bacterial methionyl- tRNA synthetase required for bacterial protein synthesis, which is very different from its mammalian counterpart. MRS-2541 is the result of an arduous testing cascade of over 500 compounds requiring broad-spectrum in vitro and in vivo Gram+ activity, a low resistance frequency and minimal hERG and mitochondrial toxicity. The initial clinical indication will be acute bacterial skin and skin structure infections (ABSSSI) with clear endpoints and relatively easy enrollments. MRS-2541 is highly potent against serious pathogens such as methicillin resistant Staphylococcus aureus (MRSA), vancomycin resistant Enterococcus faecium (VRE), and Streptococcus species, with minimum inhibitory concentrations (MICs) ≤ 0.5 µg/mL, which are below those of widely used drugs such as vancomycin and linezolid. MRS-2541 has minimal cytotoxicity on mammalian cells, is well tolerated in mice at 150 mg/Kg/day, has excellent oral bioavailability, and is as efficacious as linezolid in the S. aureus and S. pyogenes thigh murine models of infection by both the oral and subcutaneous route. Specific Aim 1 will be to optimize the new 5-step synthesis from a commercially available fluorinated precursor and prepare 150 g for Aims 2-4. Aim 2 will characterize the PK/ADME profile of MRS-2541, including metabolic profiling, cytochrome inhibition, and PK in a non-rodent species. Aim 3 will more fully characterize the antibacterial profile with MIC90s vs target and some off-target organisms, as well as the determination of the driver for in vivo efficacy, which is critical for human dose projections. Finally, Aim 4 will support a GLP 28-day toxicology study in rodents along with several safety pharmacology studies. The scientific teams at University of Washington and TSRL have the combined expertise in chemistry, microbiology, pharmacology, and preclinical drug development to execute the proposed research plan. A successful project will bring forward MRS-2541 as a clinical lead candidate, representing a novel antibiotic class to address the critical public health issue of bacterial drug-resistance not only for ABSSSIs, but for a variety of serious Gram+ infections.

该基金的目的是MRS-2541的临床前开发，MRS-2541是一种新型抗生素结构。 通过新的作用机制靶向革兰氏阳性菌。MRS-2541抑制细菌甲硫氨酰- 细菌蛋白质合成所需的tRNA合成酶，这与其 哺乳动物的对应物MRS-2541是500多个测试级联的结果。 需要体外和体内广谱革兰氏阳性菌活性的化合物， 频率和最小的hERG和线粒体毒性。 最初的临床适应症将是急性细菌性皮肤和皮肤结构感染（ABSSSI）， 明确的终点和相对容易的注册。MRS-2541对严重 病原体如耐甲氧西林金黄色葡萄球菌（MRSA）、耐万古霉素 屎肠球菌（VRE）和链球菌，最低抑菌浓度 （MIC）≤ 0.5 µ g/mL，低于广泛使用的药物，如万古霉素和 利奈唑胺。MRS-2541对哺乳动物细胞的细胞毒性极低，在150 ℃下在小鼠中耐受良好 mg/Kg/天，具有优异的口服生物利用度，并且在S.金黄色 和s.通过口服和皮下途径感染化脓性大腿鼠模型。 具体目标1将是优化新的5步合成， 氟化前体并制备150 g用于目标2 - 4。目的2将描述PK/ADME特征 MRS-2541，包括非啮齿类动物中的代谢特征、细胞色素抑制和PK 物种目的3将更全面地表征抗菌特征，MIC 90与目标值相比， 脱靶微生物，以及确定体内疗效的驱动因素，这是至关重要的 用于人体剂量预测。最后，目标4将支持啮齿动物GLP 28天毒理学研究 沿着几项安全药理学研究。 华盛顿大学和TSRL的科学团队拥有以下方面的综合专业知识： 化学、微生物学、药理学和临床前药物开发， 提出研究计划。一个成功的项目将使MRS-2541成为临床领导者 候选人，代表一种新的抗生素类，以解决关键的公共卫生问题， 细菌耐药性不仅对ABSSSI，而且对各种严重的革兰氏阳性菌感染。