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，但由于尚未发现具有细菌选择性的IMPDH抑制剂，IMPDH抑制剂尚未被用于抗菌应用。我们一直从事药物化学项目，开发以impdh为靶点的药物，用于治疗B类寄生虫小隐孢子虫。我们已经有了低纳摩尔的小弧菌IMPDH （CpIMPDH）抑制剂，与人类酶相比，其选择性为bbbb250。令人惊讶的是，CpIMPDH与细菌的impdh关系最为密切，这表明小孢子虫通过水平转移获得了该基因。我们已经确定了一个定义易感酶的结构基序；该基序存在于多种致病菌中，包括7种其他的选择性病原体。我们提出了开发CpIMPDH抑制剂作为广谱抗生素的计划。为此，我们将确定CpIMPDH抑制剂对一组致病菌的功效，这些致病菌是根据靶酶的结构变化和细菌的渗透性来确定作用谱的（选择的药剂用粗体表示）：炭疽芽孢杆菌（革兰氏阳性）、土拉杆菌（革兰氏阴性兼性胞内）、单核增生李斯特菌（革兰氏阳性兼性胞内）、马氏伯克氏菌/假麦氏菌（革兰氏阴性兼性胞内）、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一些最严重的威胁；B.炭疽；mallei/pseudomallei和F. tularensis是制定对策的重点，耐甲氧西林金黄色葡萄球菌（MRSA）和鲍曼不动杆菌是主要的治疗挑战。

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.