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

项目摘要：广泛使用抗生素导致的多重耐药机制的演变已经受到侵蚀 最重要的一类抗生素之一，β-内酰胺类的疗效。情况尤其严峻。 在非发酵革兰氏阴性病原菌中，如铜绿假单胞菌，不仅β-内酰胺酶 酶(即PDC、PER和VIM)驱动耐药性，但外膜与外排相协调起作用 抗生素进入的巨大障碍。这项为期3年的SBIR直接到第二阶段申请的重点是完成 一种独特的邻苯二酚偶联β-内酰胺酶抑制剂(CC-BLI)系列的先导优化 提供便利进入，并提供前所未有的活动水平，以对抗多药耐药(MDR) 假单胞菌与头孢洛氮烷(目前市场名称为Zerbaxa®)联合使用时。商业广告 Zerbaxa®的介绍是静脉注射头孢洛氮联合传统的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赞免受Ambler C类假单胞菌的感染 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……里面 除了增强进入，CC-BLI系列还具有对抗丝氨酸和金属β-内酰胺酶的活性 包括那些能水解碳青霉烯类的药物。在完成导联优化时，由此产生的临床前 开发候选药物将与头孢洛氮烷(TOL)配对，后者最能支持P. 铜绿假单胞菌。这种TOL/CC-BLI候选组合将通过非GLP毒理学活动进行推进 并最终获得IND的备案和批准。 最终，这一新的组合产品将为Empiric提供一种独特的临床选择 医院普通病房和ICU耐多药非发酵菌感染的治疗及作为治疗的二线治疗 易受感染的生物。

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.