Potent Antifolates as New Therapeutics for MRSA

描述（由申请人提供）：该II期STTR提案描述了康涅狄格大学制药科学系和Promiliad Biopharma的研究人员之间的合作努力，以开发针对耐甲氧西林金黄色葡萄球菌（MRSA）和化脓链球菌的有效抗生素。我们最近完成了一项I期STTR拨款，重点是通过针对必需酶二氢叶酸还原酶（DHFR）开发对抗寄生原生动物人隐孢子虫（Cryptosporidium hominis）的药物。通过这项工作，我们开发了迄今为止报道的最有效和选择性的该酶抑制剂，并显示出对培养寄生虫的有效性。在这些针对隐孢子虫的努力的同时，我们检查了这类化合物抑制其他病原生物DHFR的普遍性，发现这种支架可以被定制以有效地靶向广泛的病原DHFR酶，包括MRSA和化脓性链球菌。我们打算利用这些生物的高知名度转移我们的第一种概念验证抗生素的重点。我们已经证明，这些化合物有效地抑制各种表型的MRSA和化脓性链球菌的生长。此外，我们已经确定了几种具有代表性抑制剂的致病性MRSA酶的高分辨率晶体结构，使我们处于进一步开发这些新抗生素的有利地位。开发一种有效的候选化合物的努力将通过三个具体目标发展。在第一个目标中，我们将完成一个初始的类似物系列，并在第二个特定目标中选择两个先导化合物进入动物研究。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），以及确定在感染动物模型中的功效。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致病性形式的选择性。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。

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.