Department of Infectious Disease, The First Affilated Hospital of Anhui Medical University, Hefei, Anhui, China.
Department of Neurology, Xiangya Hospital Central South University, Changsha, Hunan, China.
J Inorg Biochem. 2021 May;218:111381. doi: 10.1016/j.jinorgbio.2021.111381. Epub 2021 Feb 20.
This study investigated whether captopril can reverse drug resistance in metallo-β-lactamase (MBL)-producing carbapenem-resistant Klebsiella pneumoniae (CRKP) and increase their sensitivity to antimicrobial agents. And also aimed to further characterize the affinity of captopril for imipenemase 4 (IMP-4) to explore the drug resistance treatment of MBL-producing bacteria. Five clinically isolated MBL-producing strains of CRKP were screened and the combined effects of captopril and meropenem were examined in vitro and in vivo to analyze whether captopril can reverse antimicrobial resistance in drug-resistant bacteria. Additionally, enzyme inhibition kinetics was analyzed to characterize the affinity of captopril for IMP-4. In MBL-producing Klebsiella pneumoniae, combined treatment with captopril significantly reduced the minimum inhibitory concentration (MIC) of carbapenems to 1 μg/mL at least, and captopril inhibited New-Delhi metallo-β-lactamase 1 (NDM-1) and IMP-4 in a concentration-dependent manner in vitro. Following the infection of Galleria mellonella by IMP-expressing bacteria, the survival rates were significantly higher in the combination treatment group than in the monotherapy groups. And the bacterial load in the combination treatment group was significantly lower than those in the monotherapy groups and IMP-4-producing bacteria were more sensitive to the combination treatment than NDM-1-producing bacteria. Additionally, enzyme inhibition kinetics firstly illustrated that the half-maximal inhibitory concentration of captopril for IMP-4 was 26.34 μM, and the dissociation constant was 37.14 μM. In brief, captopril potentiated meropenem activity and restored its efficacy against MBL-producing CRKP. Additionally, analysis of enzyme inhibition kinetics confirmed that captopril has good inhibitory effects on IMP-4 activity. Therefore, captopril or its derivatives may have clinical utility for overcoming antibiotic resistance.
本研究旨在探讨卡托普利是否能逆转金属β-内酰胺酶（MBL）产碳青霉烯酶耐药肺炎克雷伯菌（CRKP）的耐药性，并提高其对抗菌药物的敏感性。还旨在进一步研究卡托普利与亚胺培南酶 4（IMP-4）的亲和力，以探索 MBL 产细菌的耐药性治疗。筛选了 5 株临床分离的 MBL 产 CRKP 菌株，体外和体内分析卡托普利能否逆转耐药菌的抗菌药物耐药性，检测卡托普利和美罗培南联合应用的效果。此外，还分析了酶抑制动力学，以表征卡托普利与 IMP-4 的亲和力。在 MBL 产肺炎克雷伯菌中，联合应用卡托普利可使碳青霉烯类药物的最低抑菌浓度（MIC）至少降低至 1μg/mL，卡托普利在体外以浓度依赖性方式抑制新德里金属-β-内酰胺酶 1（NDM-1）和 IMP-4。在表达 IMP 的细菌感染大蜡螟后，联合治疗组的存活率明显高于单药治疗组。联合治疗组的细菌负荷明显低于单药治疗组，且 IMP 产细菌对联合治疗的敏感性高于 NDM-1 产细菌。此外，酶抑制动力学首次表明，卡托普利对 IMP-4 的半数最大抑制浓度为 26.34μM，解离常数为 37.14μM。总之，卡托普利增强了美罗培南的活性，并恢复了其对 MBL 产 CRKP 的疗效。此外，酶抑制动力学分析证实，卡托普利对 IMP-4 活性具有良好的抑制作用。因此，卡托普利或其衍生物可能具有克服抗生素耐药性的临床应用价值。
