Division of Antimicrobial Resistance Research, Center for Infectious Diseases Research, National Institute of Infectious Diseases, National Institute of Health, Korea Disease Control and Prevention Agency, Cheongju 28159, Korea.
Department of Microbiology, School of Medicine, Kyungpook National University, Daegu 41944, Korea.
Int J Mol Sci. 2021 Nov 12;22(22):12257. doi: 10.3390/ijms222212257.
The widespread of carbapenem-resistant (CRAB) is of great concern in clinical settings worldwide. It is urgent to develop new therapeutic agents against this pathogen. This study aimed to evaluate the therapeutic potentials of compound 62520, which has been previously identified as an inhibitor of the promoter activity of , against CRAB isolates, both in vitro and in vivo. Compound 62520 was found to inhibit the expression and biofilm formation in ATCC 17978 at sub-inhibitory concentrations in a dose-dependent manner. These inhibitory properties were also observed in clinical CRAB isolates belonging to sequence type (ST) 191. Additionally, compound 62520 exhibited a bacteriostatic activity against clinical clonal complex (CC) 208 CRAB isolates, including ST191, and ESKAPE pathogens. This bacteriostatic activity was not different between STs of CRAB isolates. Bacterial clearance was observed in mice infected with bioimaging strain 24 h after treatment with compound 62520. Compound 62520 was shown to significantly increase the survival rates of both immunocompetent and neutropenic mice infected with ATCC 17978. This compound also increased the survival rates of mice infected with clinical CRAB isolate. These results suggest that compound 62520 is a promising scaffold to develop a novel therapeutic agent against CRAB infections.
碳青霉烯类耐药菌（CRAB）的广泛传播引起了全球临床领域的极大关注。迫切需要开发针对这种病原体的新治疗药物。本研究旨在评估先前被鉴定为抑制基因启动子活性的化合物 62520 对 CRAB 分离株的治疗潜力，包括在体外和体内。研究发现，化合物 62520 以剂量依赖性方式在亚抑制浓度下抑制 ATCC 17978 中的表达和生物膜形成。这些抑制特性也在属于序列型（ST）191 的临床 CRAB 分离株中观察到。此外，化合物 62520 对临床克隆复合体（CC）208 CRAB 分离株，包括 ST191 和 ESKAPE 病原体，表现出抑菌活性。CRAB 分离株 ST 之间的这种抑菌活性没有差异。在感染生物成像菌株的小鼠中，在给予化合物 62520 治疗 24 小时后观察到细菌清除。研究表明，化合物 62520 显著提高了感染 ATCC 17978 的免疫功能正常和中性粒细胞减少小鼠的存活率。该化合物还提高了感染临床 CRAB 分离株的小鼠的存活率。这些结果表明，化合物 62520 是开发针对 CRAB 感染的新型治疗药物的有前途的支架。
