IMPDH-targeted antibiotics for select agents

描述（由申请人提供）：核苷酸生物合成途径提供了丰富的药物靶标来源，如二氢叶酸还原酶，广泛使用的抗菌药物甲氧苄啶的靶标。IMP脱氢酶（IMPDH）提供了类似的治疗机会。尽管IMPDH抑制剂用于免疫抑制、癌症和抗病毒治疗，但由于尚未鉴定出细菌选择性IMPDH抑制剂，因此IMPDH抑制剂尚未用于抗菌应用。我们一直在从事药物化学项目，以开发IMPDH靶向药物，用于治疗B类寄生虫隐孢子虫。我们手头有低纳摩尔的C抑制剂。小顶PDH（CpIMPDH）与人酶相比具有>250的选择性。令人惊讶的是，CpIMPDH与细菌IMPDH的关系最为密切，这表明C. parvum通过水平转移获得该基因。我们已经确定了一个定义易感酶的结构基序;该基序存在于多种病原菌中，包括其他七种选择剂。我们提出了一个计划，开发CpIMPDH抑制剂作为更广泛的抗生素。为此，我们将确定CpIMPDH抑制剂对一组病原菌的功效，所述病原菌被选择以根据靶酶的结构变异和细菌的渗透性来定义作用谱（选择粗体的代理）：炭疽杆菌（革兰氏阳性），土拉热弗朗西斯菌（革兰氏阴性兼性细胞内），单核细胞增生李斯特菌（革兰氏阳性兼性细胞内），鼻疽伯克霍尔德菌/类鼻疽伯克霍尔德菌（革兰氏阴性兼性细胞内）、金黄色葡萄球菌（革兰氏阳性）和鲍曼不动杆菌（革兰氏阴性）。这些病原体对人类健康构成最严重的威胁; B. anthracis，Bu. mallei/pseudomallei和F.土拉菌是发展对策的首要任务，而耐甲氧西林的S. aureus（MRSA）和A.鲍曼不动杆菌存在主要的治疗挑战。

DESCRIPTION (provided by applicant): The nucleotide biosynthetic pathways provide a rich source of drug targets such as dihydrofolate reductase, the target of the widely used antibacterial drug trimethoprim. IMP dehydrogenase (IMPDH) presents a similar therapeutic opportunity. Although IMPDH inhibitors are used in immunosuppressive, cancer and antiviral therapy, as yet IMPDH inhibitors have not been exploited in antibacterial applications because no bacterial-selective IMPDH inhibitors have been identified. We have been engaged in a medicinal chemistry program to develop IMPDH-targeted drugs for treating the category B parasite Cryptosporidium parvum. We have 'in hand' low nanomolar inhibitors of C. parvum IMPDH (CpIMPDH) with >250 selectivity versus the human enzymes. Surprisingly, CpIMPDH is most closely related to bacterial IMPDHs, suggesting that C. parvum obtained this gene via horizontal transfer. We have identified a structural motif that defines susceptible enzymes; this motif is found in a wide variety of pathogenic bacteria, including seven other select agents. We propose a program to develop the CpIMPDH inhibitors as broader spectrum antibiotics. To this end, we will determine the efficacy of the CpIMPDH inhibitors against a panel of pathogenic bacteria chosen to define the spectrum of action in terms of the structural variation of the target enzyme and the permeability of the bacteria (select agents in bold): Bacillus anthracis (Gram positive), Francisella tularensis (Gram-negative facultative intracellular), Listeria monocytogenes (Gram- positive facultative intracellular), Burkholderia mallei/pseudomallei (Gram-negative facultative intracellular), Staphylococcus aureus (Gram-positive) and Acinetobacter baumannii (Gram-negative). These pathogens pose some of the most serious threats to human health; B. anthracis, Bu. mallei/pseudomallei, and F. tularensis are top priorities for countermeasure development and methicillin-resistant S. aureus (MRSA) and A. baumannii present major treatment challenges.