Antimetabolites Effective against Resistant Gram-positive Bacteria

描述（由申请人提供）：耐药病原生物的进化已经危及了许多最有价值的抗生素类别的效用，并且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）发现于20世纪50年代，现在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是一种与皮肤和皮肤结构感染（SSSI）相关的临床显著革兰氏阳性病原体。然而，TMP-SMX仅对一小部分革兰氏阳性细菌有效，而不包括与SSSI相关的其他常见病原体，如化脓性链球菌。此外，耐tmp - smx的MRSA菌株的数量也在稳步增加。窄谱和大部分抗性都与TMP的靶点二氢叶酸还原酶（DHFR）序列的变化有关。我们一直专注于开发下一代抗叶酸盐，这些抗叶酸盐是天然对tmp不敏感的化脓性葡萄球菌以及野生型和对tmp耐药的MRSA的有效抑制剂。使用基于结构的设计，我们开发了一类抗生素，称为丙炔连接抗叶酸盐（pla），它对两种病原体都有有效的抗菌活性，口服生物利用度，低水平的耐药性和对MRSA小鼠模型的有效性。在本提案中，我们描述了进一步完善该先导系列的努力，以提高覆盖范围，同时优化关键的药代动力学性质。这些努力有三个具体目标。在第一个目标中，我们评估目前pla的临床谱，研究TMP耐药的分子基础，以便更好地为化合物的优化和选择提供信息。第二个目标描述了针对不敏感和抗性形式的目标的优良类似物的设计，合成和评估。在最终目的中，选择候选化合物在小鼠感染模型中进行评估，以确定疗效和药代动力学参数。通过这项工作，我们期望确定几个有希望的候选化合物，这些化合物将对进一步的翻译开发具有吸引力。

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.