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: 10482577
• 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/10482577
• 关键词: ADME Study; Anti-Bacterial Agents; Antibiotics; Applications Grants; Bacteria; Binding Proteins; 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; Medical; Membrane; Microbiology; Multi-Drug Resistance; Mus; Organism; Pharmaceutical Chemistry; Phase; Plasma Proteins; Population; Production; Property; Pseudomonas; Pseudomonas aeruginosa; Research; Resistance; Rodent; Series; Serine; Small Business Innovation Research Grant; Solubility; System; Tazobactam; Thigh structure; Toxicology; VDAC1 gene; base; beta-Lactam Resistance; beta-Lactamase; beta-Lactams; carbapenemase; clinical candidate; cytotoxicity; inhibitor; lead optimization; lead series; 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：广泛使用抗生素导致的多种耐药机制的演变已经侵蚀 最重要的抗生素之一β-内酰胺类抗生素的疗效。情况特别可怕 在非发酵革兰氏阴性病原体如铜绿假单胞菌中，其中不仅β-内酰胺酶 酶（即，PDC，PER和Vim）驱动阻力，但与外排一致的外膜用作 抗生素进入的巨大障碍。这3年SBIR直接到第二阶段的应用中心完成 一种独特的儿茶酚结合β-内酰胺酶抑制剂（CC-BLI）系列的领先优化， 提供前所未有的多药耐药（MDR）活动水平 当与头孢洛扎（目前以Zerbaxa®销售）组合时，假单胞菌。商业 Zerbaxa®的介绍是静脉注射头孢洛扎联合传统β-内酰胺酶抑制剂 他唑巴坦;然而，他唑巴坦不能保护头孢洛扎免受Ambler C类假单胞菌衍生的 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。在 除了增强进入，CC-BLI系列还具有抗丝氨酸和金属-β-内酰胺酶的活性 包括那些水解碳青霉烯类的化合物。在完成电极导线优化时， 开发候选药物将与头孢洛扎（TOL）配对，后者最能支持在P中的强效活性。 铜绿。该候选TOL/CC-BLI组合将通过非GLP毒理学活动进行推进 并最终提交IND申请和批准。 最终，可以预见，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中治疗MDR非发酵菌感染，并作为二线治疗 易感生物