Global Antibiotic Research and Development Partnership (GARDP), 15 Chemin Camille-Vidart, 1202, Geneva, Switzerland.
Institut Pasteur Korea, 16, Daewangpangyo-ro 712 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea.
EBioMedicine. 2024 Apr;102:105073. doi: 10.1016/j.ebiom.2024.105073. Epub 2024 Mar 22.
The current pipeline for new antibiotics fails to fully address the significant threat posed by drug-resistant Gram-negative bacteria that have been identified by the World Health Organization (WHO) as a global health priority. New antibacterials acting through novel mechanisms of action are urgently needed. We aimed to identify new chemical entities (NCEs) with activity against Klebsiella pneumoniae and Acinetobacter baumannii that could be developed into a new treatment for drug-resistant infections.
We developed a high-throughput phenotypic screen and selection cascade for generation of hit compounds active against multidrug-resistant (MDR) strains of K. pneumoniae and A. baumannii. We screened compound libraries selected from the proprietary collections of three pharmaceutical companies that had exited antibacterial drug discovery but continued to accumulate new compounds to their collection. Compounds from two out of three libraries were selected using "eNTRy rules" criteria associated with increased likelihood of intracellular accumulation in Escherichia coli.
We identified 72 compounds with confirmed activity against K. pneumoniae and/or drug-resistant A. baumannii. Two new chemical series with activity against XDR A. baumannii were identified meeting our criteria of potency (EC ≤50 μM) and absence of cytotoxicity (HepG2 CC ≥100 μM and red blood cell lysis HC ≥100 μM). The activity of close analogues of the two chemical series was also determined against A. baumannii clinical isolates.
This work provides proof of principle for the screening strategy developed to identify NCEs with antibacterial activity against multidrug-resistant critical priority pathogens such as K. pneumoniae and A. baumannii. The screening and hit selection cascade established here provide an excellent foundation for further screening of new compound libraries to identify high quality starting points for new antibacterial lead generation projects.
BMBF and GARDP.
目前的新抗生素研发管道未能充分解决世界卫生组织（WHO）确定的具有全球健康优先性的耐药革兰氏阴性菌所构成的重大威胁。迫切需要具有新作用机制的新型抗菌药物。我们旨在鉴定对肺炎克雷伯菌和鲍曼不动杆菌具有活性的新化学实体（NCE），并将其开发成治疗耐药感染的新疗法。
我们开发了一种高通量表型筛选和选择级联方法，用于产生对多药耐药（MDR）肺炎克雷伯菌和鲍曼不动杆菌菌株具有活性的命中化合物。我们筛选了三家已退出抗菌药物发现但继续向其化合物库中积累新化合物的制药公司的专有化合物库中选择的化合物库。使用与大肠杆菌细胞内积累可能性增加相关的“eNTRy 规则”标准选择来自两个库中的化合物。
我们鉴定了 72 种对肺炎克雷伯菌和/或耐药鲍曼不动杆菌具有确证活性的化合物。鉴定了两种具有 XDR 鲍曼不动杆菌活性的新化学系列，符合我们的效力标准（EC≤50μM）和无细胞毒性（HepG2 CC≥100μM 和红细胞溶血 HC≥100μM）。两种化学系列的密切类似物对鲍曼不动杆菌临床分离株的活性也进行了测定。
这项工作为筛选策略的开发提供了原理证明，该策略旨在鉴定对多药耐药关键优先病原体（如肺炎克雷伯菌和鲍曼不动杆菌）具有抗菌活性的新型化学实体。这里建立的筛选和命中选择级联为进一步筛选新的化合物库提供了极好的基础，以鉴定新抗菌药物先导生成项目的高质量起点。
BMBF 和 GARDP。
