Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, United States of America.
Purdue Institute of Inflammation, Immunology, and Infectious Disease, West Lafayette, Indiana, United States of America.
PLoS One. 2018 Jun 28;13(6):e0199710. doi: 10.1371/journal.pone.0199710. eCollection 2018.
Enterococci represent one of the microbial world's most challenging enigmas. Colonization of the gastrointestinal tract (GIT) of high-risk/immunocompromised patients by enterococci exhibiting resistance to vancomycin (VRE) can lead to life-threating infections, including bloodstream infections and endocarditis. Decolonization of VRE from the GIT of high-risk patients represents an alternative method to suppress the risk of the infection. It could be considered as a preventative measure to protect against VRE infections in high-risk individuals. Though multiple agents (ramoplanin and bacitracin) have been evaluated clinically, no drugs are currently approved for use in VRE decolonization of the GIT. The present study evaluates ebselen, a clinical molecule, for use as a decolonizing agent against VRE. When evaluated against a broad array of enterococcal isolates in vitro, ebselen was found to be as potent as linezolid (minimum inhibitory concentration against 90% of clinical isolates tested was 2 μg/ml). Though VRE has a remarkable ability to develop resistance to antibacterial agents, no resistance to ebselen emerged after a clinical isolate of vancomycin-resistant E. faecium was serially-passaged with ebselen for 14 days. Against VRE biofilm, a virulence factor that enables the bacteria to colonize the gut, ebselen demonstrated the ability to both inhibit biofilm formation and disrupt mature biofilm. Furthermore, in a murine VRE colonization reduction model, ebselen proved as effective as ramoplanin in reducing the bacterial shedding and burden of VRE present in the fecal content (by > 99.99%), cecum, and ileum of mice. Based on the promising results obtained, ebselen warrants further investigation as a novel decolonizing agent to quell VRE infection.
肠球菌是微生物世界中最具挑战性的谜团之一。对胃肠道 (GIT) 中具有万古霉素 (VRE) 耐药性的肠球菌进行定植的高危/免疫功能低下患者可能导致危及生命的感染，包括血流感染和心内膜炎。对高危患者的 GIT 中 VRE 进行去定植是抑制感染风险的替代方法。它可以被认为是一种预防措施，以防止高危个体发生 VRE 感染。尽管已经评估了多种药物（雷莫拉宁和杆菌肽）的临床效果，但目前没有批准用于 GIT 中 VRE 去定植的药物。本研究评估了临床药物 ebselen 作为 VRE 去定植剂的用途。当在体外评估广谱肠球菌分离株时，发现 ebselen 与利奈唑胺一样有效（针对 90%测试的临床分离株的最小抑菌浓度为 2 μg/ml）。尽管 VRE 具有显著的能力对抗生素产生耐药性，但在万古霉素耐药粪肠球菌的临床分离株连续用 ebselen 传代 14 天后，没有出现对 ebselen 的耐药性。针对 VRE 生物膜，这是一种使细菌能够在肠道中定植的毒力因子，ebselen 显示出抑制生物膜形成和破坏成熟生物膜的能力。此外，在 VRE 定植减少模型中，ebselen 在减少粪便内容物（> 99.99%）、盲肠和回肠中 VRE 的细菌脱落和负荷方面与 ramoplanin 一样有效。基于获得的有希望的结果，ebselen 作为一种新型去定植剂来控制 VRE 感染值得进一步研究。
