IMPDH-targeted antibiotics for select agents

描述(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抑制剂被用于免疫抑制、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。我们一直在从事一个药物化学项目，以开发针对IMPDH的药物来治疗B类寄生虫微小隐孢子虫。我们手中有低纳米分子的微小隐孢子虫IMPDH抑制剂(CpIMPDH)，相对于人类酶具有&gt；250的选择性。令人惊讶的是，CpIMPDH与细菌的IMPDH关系最密切，这表明微小隐孢子虫通过水平转移获得了这个基因。我们已经确定了一个定义敏感酶的结构基序；这个基序在各种致病细菌中都有发现，包括其他七种选定的制剂。我们提出了一项开发CpIMPDH抑制剂作为更广泛谱抗生素的计划。为此，我们将确定CpIMPDH抑制剂对一组病原菌的疗效，这些病原菌是根据目标酶的结构变化和细菌的通透性来确定作用谱的(BOLD中的选择药物)：炭疽芽孢杆菌(革兰氏阳性)、图拉氏方济氏菌(革兰氏阳性)、单核细胞增生性李斯特菌(革兰氏阳性兼性细胞内)、马来伯克霍尔德氏菌/假鼻疽菌(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了最严重的威胁；炭疽杆菌。耐甲氧西林金黄色葡萄球菌(MRSA)和鲍曼不动杆菌(A.baumannii)是治疗的主要挑战。

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.