Antimetabolites Effective against Resistant Gram-positive Bacteria

描述（由申请人提供）：耐药病原微生物的进化已经损害了许多最有价值的抗生素类别的效用，并需要开发新的药物来维持我们对抗传染病的能力。甲氧苄啶-磺胺甲恶唑（TMP-SMX; Bactrim）于20世纪50年代发现，目前是治疗社区获得性耐甲氧西林金黄色葡萄球菌（MRSA）的主要口服疗法之一，MRSA是一种临床上重要的革兰氏阳性病原体，与皮肤和皮肤结构感染（SSSI）相关。然而，TMP-SMX仅对窄范围的革兰氏阳性菌有效，并且不包括与SSSI相关的其他常见病原体，如化脓性链球菌。此外，耐甲氧西林金黄色葡萄球菌（MRSA）的TMP-SMX耐药菌株数量稳步增加。窄谱和大部分耐药性都与TMP靶点二氢叶酸还原酶（DHFR）序列的变化有关。我们一直致力于开发下一代抗叶酸剂，它们是天然TMP不敏感的S。化脓菌以及野生型和TMP耐药MRSA。使用基于结构的设计，我们已经开发了一类被称为炔丙基连接的抗叶酸剂（PLA）的抗生素，其对两种病原体显示出有效的抗菌活性，口服生物利用度，低水平的耐药性和MRSA的小鼠模型中的功效。在该提案中，我们描述了进一步完善该铅系列以改善覆盖范围的努力，同时优化关键药代动力学特性。这些努力分为三个具体目标。在第一个目标中，我们评估PLA的当前临床谱，并研究TMP抗性的分子基础，以更好地为化合物优化和选择提供信息。第二个目标描述了针对靶标的不敏感和抗性形式的上级类似物的设计、合成和评价。在最终目的中，在鼠感染模型中评估选择的候选化合物以确定功效和药代动力学参数。通过这项工作，我们预计确定几个有前途的候选化合物，这将是有吸引力的进一步翻译的发展。

DESCRIPTION (provided by applicant): The evolution of resistant pathogenic organisms has compromised the utility of many of the most valuable classes of antibiotics and necessitates the development of new agents to maintain our ability to combat infectious disease. Trimethoprim-sulfamethoxazole (TMP-SMX; Bactrim), discovered in the 1950s, is now one of the mainstay oral therapies for the treatment of community-acquired methicillin-resistant Staphylococcus aureus (MRSA), a clinically significant Gram-positive pathogen associated with skin and skin structure infections (SSSI). However, TMP-SMX is only effective against a narrow range of Gram-positive bacteria and does not cover other common pathogens associated with SSSI such as Streptococcus pyogenes. Additionally, there has been a steady increase in the number of TMP-SMX-resistant strains of MRSA. Both the narrow spectrum and much of the resistance are related to changes in the sequence of dihydrofolate reductase (DHFR), the target of TMP. We have been focused on the development of next-generation antifolates that are effective inhibitors of the naturally TMP-insensitive S. pyogenes as well as the wild-type and TMP-resistant MRSA. Using structure-based design, we have developed a class of antibiotics known as the propargyl-linked antifolates (PLAs) that show potent antibacterial activity against both pathogens, oral bioavailability, low levels of resistance and efficacy in a murine model of MRSA. In this proposal, we describe efforts to further refine this lead series to improve spectrum of coverage while optimizing key pharmacokinetic properties. These efforts are described in three specific aims. In the first aim, we assess the current clinical spectrum for the PLAs and study the molecular basis of TMP resistance to better inform compound optimization and selection. The second aim describes the design, synthesis and evaluation of superior analogs against insensitive and resistant forms of the target. In the final aim, select candidate compounds are evaluated in murine infection models to determine efficacy and pharmacokinetic parameters. Through this work, we anticipate identification of several promising candidate compounds that would be attractive for further translational development.