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

基本信息

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
项目类别：
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

项目摘要

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（MRSA）和耐甲氧西林的葡萄球菌表皮（MRSE）是医院和社区中血液感染的主要原因。的确， MRSA仍然是美国抗药性细菌病原体死亡率的第二大原因。尽管存在两个机械上新型的抗生素类别来治疗这种感染（Daptomycin; DAP和DAP和 linezolid; lzd），它们在诊所的使用已有近二十年的历史并没有扭转这一趋势。此外，DAP LZD潜力的重大局限性；前者仅在临床环境中仅iv iv管理显着提高医疗保健成本，尽管IV和PO交付的后者可能会导致严重的不良反应，包括扩展使用后的骨髓抑制，并且已经出现了阻力。 Tedizolid的引入不太可能阻止LZD抗性，因为它具有LZD目标。相反，β-内酰胺抗生素历史上一直是治疗最有影响力的抗生素类细菌感染，但由于MRSA/E的出现，它们的效率已经发出。重新建立β- lactams作为革兰氏阳性细菌感染的护理疗法标准，包括MRSA/E 为临床医生提供一种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的抵抗力的策略。在最近发表的工作中，我们证明了壁teichoic酸（WTA）生物合成途径富含β -lactam增强靶标。建立在一个初步数据的坚实基础，我们的目标是：目标1（阶段1; PH1）。集中的发现努力，以识别具有效力和的化合物药代动力学（PK）优于塔洛蛋白A2，用于口服二氧甲曲霉（DCX）或IV 与imipenem（IPM）结合使用。 AIM 2（阶段2; PH2）。 SAR的扩展和命中化合物的详细表征。目标3（ph2）。从AIM 2到体内效率测试至少两种化合物的进步识别主要候选人。