Broad spectrum β-lactamase inhibitors employing a Trojan horse mechanism to rescue β-lactams against multidrug-resistant Pseudomonas aeruginosa

广谱β-内酰胺酶抑制剂采用特洛伊木马机制来拯救β-内酰胺对抗多重耐药铜绿假单胞菌

• 批准号: 10588165
• 负责人: Bin Liu
• 金额: $ 100万
• 依托单位: VENATORX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-10 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588165
• 关键词: ADME Study; Anti-Bacterial Agents; Antibiotics; Applications Grants; Bacteria; Binding Proteins; Biological; Carbapenems; Catechols; Ceftazidime; Cells; Cephalosporinase; Chemistry; Chemosensitization; Childhood; Clinical; Development; Dose; Down-Regulation; Enzymes; Epidemiology; Equus caballus; Evolution; FDA approved; Family; Formulation; Funding; General Hospitals; General Ward; Generations; Grant; Hospitals; Hydrolysis; In Vitro; Infection; Intravenous; Iron; Lead; Marketing; Medical; Membrane; Multi-Drug Resistance; Mus; Organism; Pharmaceutical Chemistry; Phase; Plasma Proteins; Population; Predisposition; Production; Property; Pseudomonas; Pseudomonas aeruginosa; Research; Resistance; Rodent; Series; Serine; Small Business Innovation Research Grant; Solubility; System; Tazobactam; Thigh structure; Toxicology; VDAC1 gene; beta-Lactam Resistance; beta-Lactamase; beta-Lactams; candidate selection; carbapenemase; cytotoxicity; inhibitor; intravenous administration; lead optimization; lead series; manufacture; multi-drug resistant pathogen; multidrug-resistant Pseudomonas aeruginosa; novel; pathogen; periplasm; pharmacokinetics and pharmacodynamics; pneumonia model; pre-clinical; preclinical development; resistance mechanism; resistant strain; scale up; success; uptake

Project Summary: Evolution of multiple resistance mechanisms from extensive use of antibiotics has eroded the efficacy of one of the most important classes of antibiotics, the β-lactams. The situation is particularly dire in non-fermenting gram-negative pathogens such as Pseudomonas aeruginosa, where not only β-lactamase enzymes (i.e., PDC, PER, and VIM) drive resistance but the outer membrane in concert with efflux serves as a formidable barrier to antibiotic entry. This 3-year SBIR Direct-to-Phase II Application centers on completing the lead optimization of a unique catechol-conjugated β-lactamase inhibitor (CC-BLI) series able to take advantage of facilitated entry and offering an unprecedented level of activity against Multidrug-Resistant (MDR) Pseudomonas when combined with ceftolozane (currently marketed as Zerbaxa®). The commercial presentation of Zerbaxa® is intravenous ceftolozane combined with the legacy β-lactamase inhibitor tazobactam; however, tazobactam fails to protect ceftolozane from Ambler class C Pseudomonas-derived cephalosporinases (PDC), as well as class A (KPC), B (VIM and NDM), and D (OXA) carbapenemase. In addition to enhanced entry the CC-BLI series has activity against serine and metallo-β-lactamase enzymes including those that hydrolyze carbapenems. At the completion of lead optimization, the resulting Preclinical Development Candidate will be paired with ceftolozane (TOL), which best supports the potent activity in P. aeruginosa. This candidate TOL/CC-BLI combination will be advanced through Non-GLP toxicology activities and eventually to IND filing and approval. Ultimately, it is envisioned that this new combination product will provide a unique clinical option for empiric therapy of MDR non-fermenter infections in the hospital general ward and ICU and as a second-line therapy for susceptible organisms.

项目摘要：抗生素的广泛使用导致多种耐药机制的演变已经受到侵蚀 最重要的一类抗生素β-内酰胺的疗效情况尤其严峻。 在非发酵革兰氏阴性病原体（例如铜绿假单胞菌）中，不仅有 β-内酰胺酶 酶（即 PDC、PER 和 VIM）会产生耐药性，但外膜与外排相结合，充当 抗生素进入的巨大障碍是为期 3 年的 SBIR Direct-to-Phase II 申请的重点是完成 对独特的儿茶酚共轭 β-内酰胺酶抑制剂 (CC-BLI) 系列进行先导优化，能够利用 便利进入并提供前所未有的抗多重耐药性 (MDR) 活动水平 与ceftolozane（目前以Zerbaxa® 上市）结合使用时的假单胞菌。 Zerbaxa® 的介绍是静脉注射头孢曲嗪与传统 β-内酰胺酶抑制剂的组合 他佐巴坦；然而，他佐巴坦不能保护头孢特啰嗪免受 Ambler C 类假单胞菌衍生的侵害 头孢菌素酶 (PDC)，以及 A 类 (KPC)、B 类（VIM 和 NDM）和 D 类 (OXA) 碳青霉烯酶。 除了增强进入能力外，CC-BLI 系列还具有对抗丝氨酸和金属-β-内酰胺酶的活性 包括那些水解碳青霉烯类药物。在先导化合物优化完成后，产生的临床前药物。 开发候选药物将与ceftolozane (TOL) 配对，后者最能支持 P. 该候选 TOL/CC-BLI 组合将通过非 GLP 毒理学活动进行推进。 并最终进行 IND 备案和批准。 最终，预计这种新的组合产品将为经验性治疗提供独特的临床选择 在医院普通病房和 ICU 治疗 MDR 非发酵菌感染，并作为二线治疗 易感生物体。