Potent Antifolates as New Therapeutics for MRSA

有效的抗叶酸剂作为 MRSA 的新疗法

• 批准号: 8089567
• 负责人: Dennis L. Wright
• 金额: $ 76.37万
• 依托单位: PROMILIAD BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8089567
• 关键词: Animal Model; Animals; Anti-Bacterial Agents; Antibiotics; Award; Bacteria; Biological; Biological Availability; Collaborations; Complex; Connecticut; Cryptosporidiosis; Cryptosporidium; Development; Dihydrofolate Reductase; Dose; Drug Kinetics; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Evaluation; Exhibits; Folic Acid Antagonists; Generations; Genetic Materials; Grant; Growth; Half-Life; Homologous Gene; Human; In Vitro; Infection; Lead; Link; Methicillin Resistance; Montana; Nature; New Agents; Organism; Parasites; Pharmaceutical Chemistry; Pharmacologic Substance; Phase; Phenotype; Positioning Attribute; Property; Protozoa; Reporting; Research Personnel; Resistance; Resolution; Science; Series; Skin Tissue; Small Business Technology Transfer Research; Soft Tissue Infections; Staging; Staphylococcus aureus; Streptococcus pyogenes; Structure; Therapeutic; Universities; Work; analog; base; biodefense; chemotherapy; design; diaminopyrimidine; efficacy evaluation; fungus; improved; in vivo; indexing; inhibitor/antagonist; lead series; meetings; novel; novel therapeutics; pathogen; public health relevance; research study; resistant strain; scaffold

DESCRIPTION (provided by applicant): This Phase II STTR proposal describes a collaborative effort between researchers in the Department of Pharmaceutical Sciences at the University of Connecticut and Promiliad Biopharma to develop efficacious antibiotics targeting both methicillin-resistant strains of Staphylococcus aureus (MRSA) and Streptococcus pyogenes. We have recently completed a Phase I STTR grant that was focused on developing agents against the parasitic protozoan Cryptosporidium hominis by targeting the essential enzyme dihydrofolate reductase (DHFR). Through this work we developed the most potent and selective inhibitors of this enzyme reported to date and showed efficacy against the cultured parasite. In parallel with these efforts targeting Cryptosporidium, we examined the generality of this compound class to inhibit DHFR from other pathogenic organisms and found that this scaffold can be customized to potently target a wide range of pathogenic DHFR enzymes, including that from MRSA and Streptococcus pyogenes. We intend to capitalize on the high-profile nature of these organisms by switching the focus of our first proof-of-concept antibiotic. We have shown that the compounds effectively inhibit the growth of various phenotypes of MRSA and Streptococcus pyogenes. Moreover, we have determined several high-resolution crystal structures of the pathogenic MRSA enzyme in complex with representative inhibitors, placing us in a strong position to further develop these new antibiotics. The efforts to develop an efficacious candidate compound will evolve through three specific aims. In the first Aim, we will complete an initial analog series and select two lead compounds to move forward into animal studies in the second specific aim. These studies will determine key pharmacokinetic parameters (bioavailability, half-life) for our compounds as well as determine efficacy in an animal model of infection. In the third specific aim, we will explore new, structure-based designs to enhance the selectivity of our compounds for the pathogenic forms of DHFR over the human homolog. Completion of these studies will position us to attract outside investors and partners to progress our compounds for an IND application. PUBLIC HEALTH RELEVANCE: Despite decades of work on the discovery of antibiotics, the continued emergence of resistance organisms threatens to render many of our best antibiotics obsolete. We are working to develop new agents against that function as effective monotherapies against the methicillin-resistant strain of Staphylococcus aureus (MRSA) and Streptococcus pyogenes. Specifically we are targeting the essential enzyme dihydrofolate reductase (DHFR) that is required by the bacteria to synthesize key components needed to replicate its genetic material.

描述（由申请人提供）：本II期STTR提案描述了康涅狄格大学药学系研究人员与Promiliad Biologyma合作开发针对金黄色葡萄球菌（MRSA）和化脓性链球菌耐甲氧西林菌株的有效抗生素。我们最近完成了一期STTR拨款，重点是通过靶向必需酶二氢叶酸还原酶（DHFR）开发针对寄生原生动物人隐孢子虫的药物。通过这项工作，我们开发了迄今为止报道的这种酶的最有效和选择性的抑制剂，并显示出对培养的寄生虫的功效。在这些针对隐孢子虫的努力的同时，我们检查了这种化合物类抑制来自其他病原生物的DHFR的一般性，并发现这种支架可以定制为有效地靶向广泛的病原DHFR酶，包括来自MRSA和化脓性链球菌的DHFR酶。我们打算通过改变我们第一个概念验证抗生素的焦点来利用这些生物体的高调性质。我们已经表明，化合物有效地抑制MRSA和化脓性链球菌的各种表型的生长。此外，我们已经确定了致病性MRSA酶与代表性抑制剂复合的几种高分辨率晶体结构，使我们在进一步开发这些新抗生素方面处于有利地位。开发有效候选化合物的努力将通过三个具体目标进行。在第一个目标中，我们将完成一个初始的类似物系列，并选择两个先导化合物进入第二个特定目标的动物研究。这些研究将确定我们的化合物的关键药代动力学参数（生物利用度，半衰期），并确定在感染动物模型中的疗效。在第三个具体目标中，我们将探索新的基于结构的设计，以提高我们的化合物对DHFR致病形式的选择性。这些研究的完成将使我们能够吸引外部投资者和合作伙伴来推进我们的化合物的IND申请。 公共卫生相关性：尽管在抗生素的发现上进行了数十年的工作，但耐药微生物的持续出现有可能使我们许多最好的抗生素过时。我们正在努力开发新的药物，作为有效的单一疗法，对耐甲氧西林金黄色葡萄球菌（MRSA）和化脓性链球菌菌株。具体来说，我们针对的是细菌合成复制其遗传物质所需的关键成分所需的必需酶二氢叶酸还原酶（DHFR）。