In vitro and in vivo activities of the carbonic anhydrase inhibitor, dorzolamide, against vancomycin-resistant enterococci.
In vitro and in vivo activities of the carbonic anhydrase inhibitor, dorzolamide, against vancomycin-resistant enterococci.
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作者：
Abutaleb NS;Elhassanny AEM;Flaherty DP;Seleem MN
耐万古霉素肠球菌（VRE）是一种严重的公共卫生威胁，也是医疗相关感染的主要原因。细菌对推荐用于治疗肠球菌感染的抗生素的耐药性使这些感染的管理复杂化。因此，迫切需要发现新的抗VRE剂。我们以前报道过碳酸酐酶抑制剂（CAIs）作为新的有效的VRE抑制剂。在本研究中，评价了CAI多佐胺在体外和体内对VRE的活性。多佐胺对一组临床VRE分离株表现出强效活性，最低抑制浓度（MIC）值范围为1 µg/mL至8 µg/mL。一项杀灭动力学实验确定，多佐胺对VRE表现出抑菌作用，与选择药物（利奈唑胺）相似。多佐胺与庆大霉素对4种VRE菌株具有协同作用，与庆大霉素对6种VRE菌株具有相加作用，使庆大霉素的MIC降低数倍。此外，在体内VRE定植减少小鼠模型中，多佐胺优于利奈唑胺。给药3天和5天后，多佐胺使小鼠粪便样本中的VRE负荷分别显著降低2.9-log 10（99.9%）和3.86-log 10（99.99%）。此外，多佐胺降低了小鼠盲肠（降低1.74-log 10（98.2%））和回肠内容物（降低1.5-log 10（96.3%））中的VRE计数，其上级优于利奈唑胺。总的来说，这些结果表明，多佐胺是一种有前景的治疗选择，值得考虑作为VRE感染当前治疗方法的补充。
Vancomycin-resistant enterococci (VRE) are a serious public health threat and a leading cause of healthcare-associated infections. Bacterial resistance to antibiotics recommended for the treatment of enterococcal infections complicates the management of these infections. Hence, there is a critical need for the discovery of new anti-VRE agents. We previously reported carbonic anhydrase inhibitors (CAIs) as new potent VRE inhibitors. In the present study, the activity of the CAI, dorzolamide was evaluated against VRE both in vitro and in vivo. Dorzolamide exhibited potent activity against a panel of clinical VRE isolates, with minimum inhibitory concentration (MIC) values ranging from 1 µg/mL to 8 µg/mL. A killing kinetics experiment determined that dorzolamide exhibited a bacteriostatic effect against VRE, which was similar to the drug of choice (linezolid). Dorzolamide interacted synergistically with gentamicin against four strains of VRE, and exhibited an additive interaction with gentamicin against six VRE strains, reducing gentamicin’s MIC by several folds. Moreover, dorzolamide outperformed linezolid in an in vivo VRE colonization reduction mouse model. Dorzolamide significantly reduced the VRE burden in fecal samples of mice by 2.9-log10 (99.9%) and 3.86-log10 (99.99%) after 3 and 5 days of treatment, respectively. Furthermore, dorzolamide reduced the VRE count in the cecal (1.74-log10 (98.2%) reduction) and ileal contents (1.5-log10 (96.3%)) of mice, which was superior to linezolid. Collectively, these results indicate that dorzolamide represents a promising treatment option that warrants consideration as a supplement to current therapeutics used for VRE infections.