Development of Aminospectinomycins for Biodefense

描述（由申请人提供）：从数字上讲，抗菌药物发现中最成功的策略是对天然产物进行合成修饰，以生产新的半合成抗生素。然而，这种方法只成功地应用于少数精选的支架。重新审视这种方法，我们重点研究了低分子量抗生素大观霉素，尽管它具有安全的药理学特征，但我们认为它被忽视了。Spectinomycin是一种氨基环醇类抗生素，通过与30S核糖体结合在一个独特的位点上特异性抑制细菌蛋白质合成，该位点在细菌病原体中高度保守。虽然大观霉素在无细胞检测中是有效的，但它的临床应用仅限于淋病奈瑟菌感染的二线治疗。在20世纪80年代，人们曾尝试开发大观霉素类似物，结果发现了trospectinomycin，该药物对不同细菌病原体的活性有所提高，并进入后期临床试验，然后因商业原因被撤回，这证实了修改该核心以获得更有效的药物的潜力。鉴于最近在半合成广谱大观霉素类似物检测时不存在的多重耐药细菌的增加，我们重新研究了开发新型大观霉素类似物作为耐药生物治疗的潜力。在最近的工作中，我们发现大霉素核心易于进行高级合成修饰，产生了几个系列的类似物，这些类似物保持了大霉素优异的核糖体亲和力，并进入30S核糖体Helix 34和核糖体蛋白RpsE环的界面上的独特结合袋。这些化合物具有良好的安全性和远优于大观霉素的化学稳定性。在这些努力中，我们最近发现了一系列新的芳基取代氨基大观菌素，具有良好的抗菌活性。最有效的化合物在我们的初始设置显示：良好的广谱抗菌活性，包括活性对

DESCRIPTION (provided by applicant): Numerically, the most successful strategy in antibacterial drug discovery has been the synthetic modification of natural products to produce new semisynthetic antibiotics. However, this approach has only been successfully applied to a few select scaffolds. Revisiting this approach, we have focused on examining the low molecular weight antibiotic spectinomycin, which we felt had been neglected, in spite of its safe pharmacological profile. Spectinomycin is an aminocyclitol antibiotic that specifically inhibits bacterial protein synthesis by binding to 30S ribosome at a unique site that is highly conserved across bacterial pathogens. Although, spectinomycin is potent in cell free assays its clinical use it restricted to second line treatment for Neisseria gonorrhoeae infections. Previous attempts to develop spectinomycin analogs, in the 1980s, led to the discovery of trospectinomycin, which showed improved activity against different bacterial pathogens and progressed into late stage clinical trials before being withdrawn for commercial reasons, validating the potential to modify this core to obtain more potent generations of drug. In view of the recent rise in multi-drug resistant bacteria that were not present when semi-synthetic broad spectrum spectinomycin analogs were last examined, we reinvestigated the potential for developing novel spectinomycin analogs as treatments for drug resistant organisms. In recent work we have found spectinomycin core tractable for advanced synthetic modifications producing several series of analogs that maintain the excellent ribosomal affinity of spectinomycin and access a unique binding pocket at the interface of 30S ribosome Helix 34 and a loop of ribosomal protein RpsE. These compounds have an excellent safety profile and far superior chemical stability to spectinomycin. In these efforts, we have recently discovered a novel series of aryl substituted aminospectinomycins with good antibacterial activities. The most potent of our compounds in our initial set demonstrate: good broad spectrum anti-bacterial activity including activity against NIAID priority biodefense pathogens; on target inhibition of protein synthesis; good pharmacokinetic profiles; and excellent anti-S. pneumoniae activity in vivo. We believe the aminospectinomycins represent an important rediscovery of a neglected chemotype that can be used for the treatment of drug resistant and biodefense infections. The further development of this series will be pursued in three aims to: (i) Perform further structure based design and synthesis of novel aminospectinomycins with high antibacterial potency in seven targeted subseries; (ii) Confirm the mode of action of emerging leads and study the potential for cross resistance and inactivation; (iii) Perform lead development through five stages of detailed tests that include a full antimicrobial assessment, in vitro ADME, pharmacokinetic testing, toxicologic and in vivo efficacy experiments. After each stage, the data will be used to guide the design and synthesis of future generations of compounds and to select the best compounds to move on to the next stage such that viable, well characterized drug candidates will emerge from this study suitable for preclinical development.