Advancement to IND of novel BLI for pairing with cefixime

项目概要/摘要。 β-内酰胺抗生素是美国使用最广泛的抗生素类别，占到了50%以上， 抗菌处方除其他作用外，它们是治疗因感染而难以治疗的感染的关键疗法。 革兰氏阴性病原体如E.大肠杆菌、肺炎克雷伯菌和肠杆菌属。但 新型β-内酰胺酶的惊人传播正在迅速损害这类抗生素的效用 耐药机制;由细菌产生的水解β-内酰胺抗生素的酶。一 特别重要的问题是缺乏口服生物可利用的β-内酰胺/β-内酰胺酶抑制剂（BLI） 能够解决这一新兴挑战的组合，无论是在生物防御竞技场， 医院/社区设置。口服β-内酰胺与传统BLI（例如， 阿莫西林/克拉维酸或Augmentin®）对革兰氏阴性病原体表现出合理的活性 表达Ambler A类超广谱β-内酰胺酶（ESBLs），但缺乏抗微生物活性 表达A类碳青霉烯酶（KPC型）、C类头孢菌素酶（染色体和质粒） 和D类苯唑西林酶。我们已经确定了一个化合物系列具有强大的和广谱的活性 针对这些丝氨酸β-内酰胺酶。这些化合物拯救了口服生物可利用的化合物的活性。 头孢菌素头孢克肟在革兰氏阴性肠杆菌科的MDR菌株中，包括E. coli和K. 肺炎。此外，我们已经表明，原型前药在系列中表现出惊人的口服给药效果。 它们在啮齿动物中的生物利用度，以及它们在细菌性疾病的鼠模型中拯救头孢克肟活性。的 本项目的目标是将选定的开发候选产品推进IND申报，以用于 与头孢克肟联用。

Project Summary/Abstract. β-lactam antibiotics are the most widely used antibiotic class in the U.S., accounting for more than 50% of antibacterial prescriptions. Among other roles, they are critical therapeutics for difficult-to-treat infections due to gram negative pathogens such as E. coli, Klebsiella pneumoniae, and Enterobacter spp. However, the utility of this class of antibiotics is being rapidly compromised by the alarming spread of new β-lactamase resistance mechanisms; enzymes produced by bacteria that hydrolytically inactivate β-lactam antibiotics. A particularly important concern is the lack of orally bioavailable β-lactam/β-lactamase inhibitor (BLI) combinations capable of addressing this emerging challenge, both in the Biodefense arena and in the hospital/community settings. Orally available β-lactam combinations with legacy BLIs (e.g., amoxicillin/clavulanic acid or Augmentin®) demonstrate reasonable activity against Gram negative pathogens expressing Ambler Class A Extended Spectrum Beta Lactamases (ESBLs), but lack activity against organisms expressing Class A carbapenemases (KPC-type), Class C cephalosporinases (chromosomal and plasmidic) and Class D oxacillinases. We have identified a compound series with potent and broad spectrum activity against these serine β-lactamases. These compounds rescue the activity of the orally bioavailable cephalosporin cefixime in MDR-strains of Gram negative Enterobacteriaceae, including E. coli, and K. pneumoniae. Moreover, we have shown that prototype prodrugs in the series demonstrate striking oral bioavailability in rodents, and that they rescue cefixime activity in murine models of bacterial disease. The objectives of this project are to advance the selected Development Candidate to IND filing for use in combination with cefixime.