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

这项资助的目标是一种新的抗生素结构mRS-2541的临床前开发。 通过一种新的作用机制靶向革兰氏+细菌。MRS-2541抑制细菌甲硫基- 细菌蛋白质合成所需的tRNA合成酶，这与它的 哺乳动物的对应物。MRS-2541是经过500多次艰苦测试的结果 化合物需要广谱的体内外活性，革兰氏+活性低，抗性低 频率和最小的HERG和线粒体毒性。 最初的临床适应症是急性细菌性皮肤和皮肤结构感染(ABSSSI)， 明确的终端和相对容易的注册。MRS-2541对严重的 病原体，如耐甲氧西林金黄色葡萄球菌(MRSA)，耐万古霉素 最低抑菌浓度的粪肠球菌(VRE)和链球菌 (MICs)≤为0.5微克/毫升，低于万古霉素和万古霉素等广泛使用的药物 利奈唑胺。MRS-2541对哺乳动物细胞的毒性最小，在150℃的小鼠体内耐受性良好 Mg/kg/天，具有极好的口服生物利用度，对金黄色葡萄球菌的疗效与利奈唑胺相当。 和化脓性链球菌通过口服和皮下途径建立小鼠大腿感染模型。 具体目标1将是优化新的5步合成，从商业上可以获得的 氟化前驱体，为AIMS 2-4制备150克。AIM 2将描述PK/ADME简介 MRS-2541在非啮齿动物中的作用，包括代谢特征、细胞色素抑制和PK 物种。目标3将更全面地描述MIC90与TARGET和一些 非靶标生物，以及体内药效驱动因素的确定，这是至关重要的 用于人体剂量预测。最后，Aim 4将支持对啮齿动物进行为期28天的GLP毒理学研究 以及几项安全药理学研究。 华盛顿大学和TSRL的科学团队在 化学、微生物学、药理学和临床前药物开发 提出了研究计划。一个成功的项目将使MRS-2541成为临床领先者 候选人，代表一种新的抗生素类别，以解决关键的公共卫生问题 细菌耐药性不仅对ABSSIS，而且对各种严重的革兰氏+感染。

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.