Inhibitors of wall teichoic acid biosynthesis of Staphylococcus aureus

金黄色葡萄球菌壁磷壁酸生物合成抑制剂

• 批准号: 8250668
• 负责人: TIMOTHY J OPPERMAN
• 金额: $ 30万
• 依托单位: MICROBIOTIX, INC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8250668
• 关键词: Ampicillin; Anabolism; Animal Model; Anti-Bacterial Agents; Antibiotics; Autolysis; Bacteria; Bacterial Drug Resistance; Biological Assay; Cell Wall; Cell division; Cells; Cessation of life; Chemicals; Chemosensitization; Clinic; Clinical; Combined Modality Therapy; Communities; Daptomycin; Development; Dimethyl Sulfoxide; Drug Delivery Systems; Drug Design; Evaluation; Exhibits; FDA approved; Failure; Frequencies; Goals; Growth; Health care facility; Hospitals; Human; Infection; Laboratories; Lead; Libraries; Life; Linezolid; Link; Lipids; Medical; Methicillin; Microbial Biofilms; Molecular Target; Monobactams; Multi-Drug Resistance; Pathway interactions; Penicillins; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Play; Polymers; Prevalence; Production; Reporting; Research; Resistance; Role; Screening procedure; Series; Specificity; Staphylococcus aureus; Structure; Surface; Technology; Teichoic Acids; Therapeutic; Toxic effect; Toxicology; United States; Vancomycin; Vancomycin Resistance; Vancomycin-resistant S. aureus; Virulence; Walkers; base; beta-Lactams; design; drug discovery; in vivo; inhibitor/antagonist; innovation; inorganic phosphate; medical schools; methicillin resistant Staphylococcus aureus; novel; novel strategies; pathogen; patient population; preclinical study; prevent; research study; small molecule; sugar; telavancin; tigecycline

DESCRIPTION (provided by applicant): The increasing prevalence of multidrug resistant infections caused by Gram-positive pathogens, such as methicillin resistant Staphylococcus aureus (MRSA), underscores the clinical need for novel strategies to treat life-threatening infections. New antibacterial drugs that are effective against MRSA have been introduced recently, but must be given intravenously, are limited to hospital use, are not tolerated well, and are already subject to resistance. The overall goal of the proposed research is discover a novel class of drugs that target the wall teichoic acid (WTA) biosynthetic pathway of S. aureus. WTAs are phosphate rich, highly anionic polymers that are covalently linked to the cell wall of most Gram-positive pathogens. Inactivation of the later enzymatic steps of the WTA pathway prevents growth, unless the pathway is blocked by inactivation of the initial enzymatic steps. Loss of WTA in S. aureus results in abnormalities in cell wall structure and cell division, and increases autolysis. WTA also plays an important role in the following aspects of virulence: host colonization, resistance to antibacterial peptides and lipids, and biofilm formation. Significantly, loss of WTA increases the sensitivity of MRSA to beta-lactam antibiotics. Potent WTA inhibitors will provide multiple therapeutic benefits, such as bacterial growth inhibition, decreased virulence, and renewed clinical utility of beta- lactam antibiotics for treating MRSA, which represents a highly significant innovation. Our strategy is to identify potent inhibitors of specific steps in the WTA biosynthetic pathway, and to develop them into antibacterial drugs that will be used in combination therapy with an FDA-approved beta-lactam antibiotic to treat S. aureus infections. In Phase I, we will modify and optimize a validated screening assay to increase the sensitivity of the assay for inhibitors of specific WTA targets. We will use this assay to screen >300,000 discreet small molecule compounds to identify inhibitors, and we will prioritize them using a panel of existing secondary assays designed to evaluate antibacterial potency, antibacterial spectrum, selectivity, frequency of resistance, and potentiation of beta-lactam antibiotics. We will verify the molecular target of high priority hits. In Phase II, we will develop the most promising validated hits into lead compounds by optimizing their activity and specificity using rational drug design. The specific aims of this proposal are as follows. Aim 1. Modify and optimize an established cell based, pathway specific screening assay to favor the identification of inhibitors of specific steps of WTA biosynthesis (TarB, D, and F). Aim 2. Screen a diverse compound library, identify, and confirm inhibitors of WTA synthesis. Aim 3. Validate confirmed inhibitors of WTA synthesis using secondary assays and identify hit series. Aim 4. Verify mechanism of action of selected hit series. PUBLIC HEALTH RELEVANCE: The goal of this research is to discover chemical compounds that can be developed into powerful drugs that will be used to treat serious infections caused by methicillin resistant Staphylococcus aureus, also known as MRSA. These new drugs will interfere with the ability of S. aureus to produce a sugar polymer, known as wall teichoic acid (WTA), which coats the outer surface of the bacterium and enables it to colonize humans and cause infection. Compounds that interfere with WTA production act as antibiotics by preventing bacterial growth, and also sensitize MRSA to the important beta lactam class of antibiotics, which includes penicillin, methicillin, and ampicillin. The successful development of innovative WTA-active drugs will be a significant advance in the treatment of MRSA infections.

描述（由申请人提供）：革兰氏阳性病原体引起的多重耐药感染日益流行，如耐甲氧西林金黄色葡萄球菌（MRSA），强调了临床需要新的策略来治疗危及生命的感染。最近已经推出了对MRSA有效的新型抗菌药物，但必须静脉注射，仅限于医院使用，耐受性不好，并且已经出现耐药性。本研究的总体目标是发现一类针对金黄色葡萄球菌壁磷壁酸（WTA）生物合成途径的新型药物。wta是富含磷酸盐的高阴离子聚合物，与大多数革兰氏阳性病原体的细胞壁共价连接。WTA途径的后期酶促步骤失活会阻止生长，除非该途径被初始酶促步骤失活阻断。金黄色葡萄球菌WTA缺失导致细胞壁结构和细胞分裂异常，并增加自溶。WTA还在以下毒力方面发挥重要作用：宿主定植、对抗菌肽和脂质的抗性以及生物膜的形成。值得注意的是，WTA的缺失增加了MRSA对β -内酰胺类抗生素的敏感性。有效的WTA抑制剂将提供多种治疗益处，如细菌生长抑制，毒性降低，以及β -内酰胺类抗生素治疗MRSA的新临床应用，这是一个非常重要的创新。我们的策略是确定WTA生物合成途径中特定步骤的有效抑制剂，并将其开发成抗菌药物，用于与fda批准的β -内酰胺抗生素联合治疗金黄色葡萄球菌感染。在I期，我们将修改和优化一个经过验证的筛选试验，以提高该试验对特定WTA靶点抑制剂的敏感性。我们将使用该方法筛选100万到30万的小分子化合物来确定抑制剂，我们将使用现有的二级分析来评估它们的抗菌效力、抗菌谱、选择性、耐药频率和β -内酰胺类抗生素的增强作用。我们将验证高优先级命中的分子靶标。在第二阶段，我们将通过合理的药物设计优化它们的活性和特异性，将最有希望的经过验证的hit开发成先导化合物。本建议的具体目的如下。目的1。修改和优化已建立的基于细胞的途径特异性筛选试验，以有利于识别WTA生物合成特定步骤的抑制剂（TarB， D和F）。目标2。筛选多种化合物库，鉴定并确认WTA合成抑制剂。目标3。使用二级分析验证已确认的WTA合成抑制剂，并确定命中系列。目标4。验证所选命中系列的作用机制。