Commercial AHAS-inhibiting herbicides are promising drug leads for the treatment of human fungal pathogenic infections
Commercial AHAS-inhibiting herbicides are promising drug leads for the treatment of human fungal pathogenic infections
复制标题
商业 AHAS 抑制性除草剂是治疗人类真菌病原感染的有希望的先导药物
DOI：
10.1073/pnas.1809422115
复制
发表时间：
2018-10-09
影响因子：
11.1
通讯作者：
Guddat, Luke W.
中科院分区：
文献类型：
--
作者：
Garcia, Mario D.;Chua, Sheena M. H.;Guddat, Luke W.
对常规疗法具有抗性的人类真菌病原体对全球人类健康构成重大威胁。因此，迫切需要发现通过新的作用机制发挥作用的新的抗真菌药物。在这里，我们表明，商业除草剂，抑制乙酰羟酸合成酶（AHAS）具有强大的和广谱的抗真菌活性在体外和氯嘧磺隆乙基，磺酰脲类除草剂家族的成员，在小鼠模型中具有抗真菌活性。因此，这项研究表明，AHAS抑制剂具有很强的潜力，被开发成有效的抗真菌治疗剂。耐药人类致病性真菌疾病的流行率增加对全球人类健康构成重大威胁。因此，迫切需要新的药物来对抗这些感染。在这里，我们证明了乙酰羟酸合成酶（AHAS），支链氨基酸生物合成途径中的第一个酶，是一个有前途的抗真菌药物发现的新靶点。首先，我们表明，几个AHAS抑制剂开发的商业除草剂是强大的累积抑制剂白色念珠菌AHAS（Ki值低至800 pM），并确定了高分辨率的晶体结构，这种酶的复杂与这些除草剂。此外，我们已经证明，氯嘧磺隆乙基（CE），磺酰脲类除草剂家族的成员，对五种不同的念珠菌属和新型隐球菌具有有效的抗真菌活性（最低抑菌浓度，50%值低至7 nM）。此外，在这些试验中，我们已经证明CE和伊曲康唑（P450抑制剂）可以协同作用，以进一步提高效力。最后，我们在白色念珠菌感染的小鼠中表明，CE在清除肺、肝和脾中的致病真菌负荷方面非常有效，从而降低了总体死亡率。因此，鉴于其对人类细胞的低毒性，AHAS抑制剂代表了一类新的抗真菌候选药物。
Significance Human fungal pathogens resistant to conventional therapeutics pose a major threat to global human health. Thus, there is an urgent need to discover new antifungal drugs that act via novel mechanisms of action. Here, we show that commercial herbicides that inhibit acetohydroxyacid synthase (AHAS) have potent and broad-spectrum antifungal activity in vitro and that chlorimuron ethyl, a member of the sulfonylurea herbicide family, has antifungal activity in a mouse model. Thus, this study shows that AHAS inhibitors have strong potential to be developed into potent antifungal therapeutic agents. The increased prevalence of drug-resistant human pathogenic fungal diseases poses a major threat to global human health. Thus, new drugs are urgently required to combat these infections. Here, we demonstrate that acetohydroxyacid synthase (AHAS), the first enzyme in the branched-chain amino acid biosynthesis pathway, is a promising new target for antifungal drug discovery. First, we show that several AHAS inhibitors developed as commercial herbicides are powerful accumulative inhibitors of Candida albicans AHAS (Ki values as low as 800 pM) and have determined high-resolution crystal structures of this enzyme in complex with several of these herbicides. In addition, we have demonstrated that chlorimuron ethyl (CE), a member of the sulfonylurea herbicide family, has potent antifungal activity against five different Candida species and Cryptococcus neoformans (with minimum inhibitory concentration, 50% values as low as 7 nM). Furthermore, in these assays, we have shown CE and itraconazole (a P450 inhibitor) can act synergistically to further improve potency. Finally, we show in Candida albicans-infected mice that CE is highly effective in clearing pathogenic fungal burden in the lungs, liver, and spleen, thus reducing overall mortality rates. Therefore, in view of their low toxicity to human cells, AHAS inhibitors represent a new class of antifungal drug candidates.