Pcovery, Copenhagen, Denmark.
Instituto de Biología Funcional y Genómica, Consejo Superior de Investigaciones Científicas, Salamanca, Spain.
Antimicrob Agents Chemother. 2018 Apr 26;62(5). doi: 10.1128/AAC.02024-17. Print 2018 May.
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 antifungal activity and 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 zinc-attenuating compounds (ZACs), to have strong affinity for zinc, and their growth inhibitory effects on and 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 zinc uptake system, thus supporting perturbance of zinc homeostasis as the likely mode of action. With demonstrated and 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.
发病率罕见但难以治疗的侵袭性真菌病原体的增加以及对现有抗真菌药物的耐药性，要求具有新型作用机制的新型广谱抗真菌药物。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，它们在真菌肾脏负担念珠菌病模型中表现出广谱抗真菌活性和功效。这些化合物是在旨在寻找新型真菌质膜质子 ATP 酶 Pma1 抑制剂的药物发现过程中偶然发现的。基于它们的结构，我们假设它们可能作为锌螯合剂起作用。事实上，荧光基于亲和力测定和电位测定都表明这些化合物随后被称为锌衰减化合物 (ZAC)，对锌具有很强的亲和力，并且它们对 和 的生长抑制作用可以通过向真菌生长培养基中添加外源锌来失活。我们确定 ZAC 是抑菌剂，不易产生耐药性。基因表达分析表明，ZAC 干扰编码主要锌摄取系统成分的基因的表达，因此支持锌稳态失调作为可能的作用模式。具有证明的 和 抗真菌活性、不易产生耐药性发展以及新型作用模式，ZAC 代表了一类有前途的新型抗真菌化合物，因此值得在药物开发计划中推进。
