...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Antimicrobial agents and chemotherapy. >Novel Zinc-Attenuating Compounds as Potent Broad-Spectrum Antifungal Agents with In Vitro and In Vivo Efficacy
【24h】

Novel Zinc-Attenuating Compounds as Potent Broad-Spectrum Antifungal Agents with In Vitro and In Vivo Efficacy

机译：新型锌衰减化合物作为具有体外和体内效力的有效的宽谱抗真菌剂

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

An increase in the incidence of rare but hard-to-treat invasive fungal pathogens as well as resistance to the currently available antifungal drugs calls for new broad-spectrum antifungals with a novel mechanism of action. Here we report the identification and characterization of two novel zinc-attenuating compounds, ZAC307 and ZAC989, which exhibit broad-spectrum in vitro antifungal activity and in vivo efficacy in a fungal kidney burden candidiasis model. The compounds were identified serendipitously as part of a drug discovery process aimed at finding novel inhibitors of the fungal plasma membrane proton ATPase Pma1. Based on their structure, we hypothesized that they might act as zinc chelators. Indeed, both fluorescence-based affinity determination and potentiometric assays revealed these compounds, subsequently termed zincattenuating compounds (ZACs), to have strong affinity for zinc, and their growth inhibitory effects on Candida albicans and Aspergillus fumigatus could be inactivated by the addition of exogenous zinc to fungal growth media. We determined the ZACs to be fungistatic, with a low propensity for resistance development. Gene expression analysis suggested that the ZACs interfere negatively with the expression of genes encoding the major components of the A. fumigatus zinc uptake system, thus supporting perturbance of zinc homeostasis as the likely mode of action. With demonstrated in vitro and in vivo antifungal activity, low propensity for resistance development, and a novel mode of action, the ZACs represent a promising new class of antifungal compounds, and their advancement in a drug development program is therefore warranted.
机译：罕见但难以治疗的侵入性真菌病原体的发病率的增加以及对目前可用的抗真菌药物的抵抗力呼吁具有新的抗谱的新型作用机制。在这里，我们报告了两种新型锌衰减化合物，ZAC307和ZAC989的鉴定和表征，其在真菌肾负担念珠菌病模型中表现出广谱体外抗真菌活性和体内疗效。作为针对药物发现过程的一部分鉴定该化合物，其旨在发现真菌血浆膜质子ATP酶PMA1的新抑制剂。根据他们的结构，我们假设他们可能充当锌螯合剂。实际上，基于荧光的亲和测定和电位测定均显示出这些化合物，随后被称为ZINCATTEN化合物（ZACS），对锌具有很强的亲和力，并且它们通过添加外源性锌来灭活对念珠菌和曲霉的生长抑制作用。对真菌生长媒体。我们确定了ZAC，具有耐受性的低抗性倾向。基因表达分析表明，Zacs对编码A.Fumigatus锌摄取系统的主要成分的基因的表达干扰，从而支持锌稳态的扰动作为可能的作用方式。随着体外和体内抗真菌活性的说明，抗性发育的低倾向和新的动作模式，ZACS代表着新的新类抗真菌化合物，因此因此有必要进行药物开发计划的进步。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号