Restoring Beta-lactam efficacy against methicillin-resistant Staphylococci

恢复 β-内酰胺对耐甲氧西林葡萄球菌的功效

• 批准号: 9814432
• 负责人: Terry Roemer
• 金额: $ 100万
• 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 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9814432
• 关键词: Address; Adjuvant; Adverse effects; Anabolism; Antibiotics; Area Under Curve; Bacterial Infections; Biological Availability; Cell Wall; Cell division; Chemicals; Chemosensitization; Clinic; Clinical; Communities; Cytochromes; Daptomycin; Data; Development; Dose; Drug Kinetics; Drug resistance; Enzymes; Fasting; Formulation; Foundations; Genus staphylococcus; Goals; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Growth; Half-Life; Health Care Costs; Hospitals; Imipenem; In Vitro; Infection; Intestines; Intravenous; Ion Channel; Life; Linezolid; Liquid substance; Maximum Tolerated Dose; Measures; Methicillin Resistance; Microbial Biofilms; Minimum Inhibitory Concentration measurement; Modeling; Monobactams; Mus; Myelosuppression; Oral; Pathway interactions; Phase; Play; Polymers; Predisposition; Property; Publishing; Reporting; Resistance; Role; Sepsis; Septicemia; Series; Solid; Solubility; Staphylococcus aureus; Staphylococcus epidermidis; Structure-Activity Relationship; Taro Vegetable; Teichoic Acids; Testing; Therapeutic; Thigh structure; Toxic effect; United States; Virulence; Work; analog; aqueous; bactericide; base; beta-Lactam Resistance; beta-Lactamase; beta-Lactams; clinical development; cytotoxicity; efficacy study; efficacy testing; in vivo; inhibitor/antagonist; lead candidate; methicillin resistant Staphylococcus aureus; mortality; novel; novel strategies; novel therapeutics; pathogen; pathogenic bacteria; physical property; preclinical evaluation; resistance frequency; standard of care; synergism; theories; trend

Methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE) are a major cause of bloodstream infections in the hospital and in the community. Indeed, MRSA remains the second leading cause of mortality by drug-resistant bacterial pathogens in the USA. Although two mechanistically novel antibiotic classes exist to treat such infections (Daptomycin; DAP and Linezolid; LZD), their use in the clinic for nearly two decades has not reversed this trend. Moreover, DAP and LZD possess significant limitations; the former is solely IV-administered in a clinical setting, which significantly increases health care costs, and the latter, although delivered by IV and PO, can cause serious adverse effects, including myelosuppression following extended use, and resistance has emerged. The introduction of tedizolid is not likely to thwart LZD resistance since it shares the LZD target. Conversely, β-lactam antibiotics have historically served as the most impactful class of antibiotics 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 a new therapeutic option addressing these issues and offer an antibiotic stewardship strategy to mitigate resistance to DAP and LZD. In recently published work, we have demonstrated that the Wall Teichoic Acid (WTA) biosynthetic pathway is rich in β -lactam potentiation targets. Building upon a solid foundation of preliminary data, our Aims are: Aim 1 (Phase 1; Ph1). Focused discovery effort to identify compounds with potency and pharmacokinetics (PK) superior to tarocin A2, for oral combination with dicloxacillin (DCX) or IV combination with imipenem (IPM). Aim 2 (Phase 2; Ph2). Expansion of SAR and detailed characterization of hit compounds. Aim 3 (Ph2). Advancement of at least two compounds from Aim 2 through in vivo efficacy testing to identify lead candidates.

耐甲氧西林金黄色葡萄球菌和耐甲氧西林表皮葡萄球菌 (MRSE)是医院和社区血液感染的主要原因。的确， 在美国，耐甲氧西林金黄色葡萄球菌仍然是耐药细菌致死的第二大原因。 尽管存在两种机械上新颖的抗生素类来治疗这种感染(达托霉素；DAP和 利奈唑胺；LZD)，它们在临床上的使用近20年并没有扭转这一趋势。此外，DAP 和LZD有很大的局限性；前者只在临床环境下静脉注射，这 显著增加了医疗保健成本，后者虽然由静脉注射和PO提供，但可能会导致 严重的不良反应，包括长期使用后的骨髓抑制，并出现了耐药性。 替氮唑胺的引入不太可能阻止LZD的耐药性，因为它与LZD的目标相同。 相反，β-内酰胺类抗生素历来是治疗效果最好的一类抗生素 细菌感染，但其疗效已被耐甲氧西林金黄色葡萄球菌/E的出现侵蚀。重建β- 内酰胺类药物作为包括MRSA/E在内的革兰氏阳性细菌感染的标准护理疗法 为临床医生提供解决这些问题的新治疗选择，并提供抗生素管理 减轻对DAP和LZD耐药性的策略。在最近出版的著作中，我们已经证明了 壁磷壁酸的生物合成途径中含有丰富的β-内酰胺增强靶点。建立在 初步数据基础雄厚，我们的目标是： 目标1(阶段1；PH1)。专注于发现具有效力和活性的化合物 口服与双氯西林(DCX)或静脉注射的药代动力学(PK)优于Tarocin A2 与亚胺培南(IPM)联合应用。 目标2(阶段2；PH2)。合成孔径雷达的扩展和HIT化合物的详细表征。 目标3(PH2)。至少两种来自AIM 2的化合物通过体内药效试验的进展 确定主要候选人。