Broad-spectrum, Orally Bioavailable Beta-lactamase Inhibitors for Biodefense

用于生物防御的广谱、口服生物可利用的 β-内酰胺酶抑制剂

• 批准号: 8833245
• 负责人: Christopher John Burns
• 金额: $ 144.88万
• 依托单位: VENATORX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8833245
• 关键词: Accounting; Address; Advanced Development; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Antibiotics; Back; Bacteria; Bacterial Infections; Bioavailable; Biological Assay; Biological Availability; Biology; Canis familiaris; Cardiotoxicity; Categories; Cephalosporins; Chemistry; Chromosome abnormality; Clinical; Clinical Microbiology; Development; Development Plans; Dose; Employee Strikes; Enterobacter; Enterobacteriaceae; Enzymes; Epidemiology; Escherichia coli; Generations; Health; Hospitals; Human; In Vitro; Infection; Intestines; Intravenous; Klebsiella; Klebsiella pneumonia bacterium; Lactamase; Lactams; Liver; Metabolic Biotransformation; Microsomes; Modeling; Monkeys; Monobactams; Mus; National Institute of Allergy and Infectious Disease; Oral; Organism; Parents; Permeability; Pharmaceutical Preparations; Pharmacology; Preparation; Prodrugs; Production; Property; Rattus; Reporting; Resistance; Rodent; Role; Route; Safety; Salmonella; Salmonella infections; Septicemia; Series; Serine; Serum; Shigella; Testing; Therapeutic; Thigh structure; Toxicology; base; beta-Lactamase; biodefense; community setting; design; efficacy testing; genotoxicity; in vivo; inhibitor/antagonist; micronucleus; novel; pathogen; pre-clinical; programs; prospective; prototype; resistance mechanism; resistant strain; respiratory; scale up

DESCRIPTION (provided by applicant):ß-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 Salmonella spp., Shigella spp., 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 ß-lactamase resistance mechanisms; enzymes produced by bacteria that hydrolytically inactivate ß-lactam antibiotics. A particularly important concern is te lack of orally bioavailable ß-lactam/ß- lactamase inhibitor (BLI) combinations capable of addressing this emerging challenge, both in the Biodefense arena and in the hospital/community settings. Orally available ß-lactam combinations with legacy BLIs (e.g., amoxicillin/clavulanic acid or Augmentin(R)) demonstrate some 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, including carbapenemases. We have identified a novel ß-lactamase inhibitor series with potent and broad spectrum activity against this new wave of serine ß-lactamases and high selectivity for bacteria. These compounds rescue the activity of the orally bioavailable cephalosporin Ceftibuten in MDR-strains of Gram negative Enterobacteriaceae, including Category B and C priority pathogens Salmonella spp., and MDR- E. coli and K. pneumoniae. Moreover, we have shown that designed prodrug prototypes in the series can demonstrate striking oral bioavailability in rodents, and rescue Ceftibuten activity in murine models of bacterial infection. The objectives of this project are to execute a comprehensive oral prodrug approach on the most broad- spectrum parent BLIs in the series, select the first Development Candidate (DC), and advance the selected DC to IND filing for clinical development in combination with Ceftibuten.

描述（由申请人提供）：β-内酰胺类抗生素是美国使用最广泛的抗生素类别，占抗菌处方的 50% 以上，除其他作用外，它们是治疗革兰氏阴性菌难以治疗的感染的关键药物。阴性病原体，如沙门氏菌、志贺氏菌、大肠杆菌、肺炎克雷伯菌和肠杆菌。此类抗生素正在迅速受到损害 由水解失活的细菌产生的新型β-内酰胺酶抗性机制的惊人传播； 一个特别重要的问题是，在生物防御领域和医院/社区中，缺乏能够应对这一新挑战的口服生物可利用的 β-内酰胺/β-内酰胺酶抑制剂 (BLI) 组合。 -内酰胺与传统 BLI（例如阿莫西林/克拉维酸或 Augmentin(R)）的组合表现出对表达革兰氏阴性病原体的某些活性Ambler A 类超广谱 β 内酰胺酶 (ESBL)，但对表达 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（包括碳青霉烯酶）的生物体缺乏活性，我们已鉴定出一种新型 ß-。内酰胺酶抑制剂系列，具有针对新一波丝氨酸 β-内酰胺酶的有效广谱活性，这些化合物可挽救口服生物可利用的头孢菌素头孢布烯对革兰氏阴性肠杆菌科细菌（包括 B 类和 C 类优先病原体沙门氏菌以及 MDR 大肠杆菌和肺炎克雷伯氏菌）的活性。已经表明，该系列中设计的前药原型可以在啮齿动物中表现出惊人的口服生物利用度，并在小鼠细菌模型中恢复头孢布烯的活性该项目的目标是对系列中最广谱的母体 BLI 执行全面的口服前药方法，选择第一个开发候选者 (DC)，并将选定的 DC 推进 IND 备案，以结合临床开发。头孢布烯。