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Discovery of a Novel Dibromoquinoline Compound Exhibiting Potent Antifungal and Antivirulence Activity That Targets Metal Ion Homeostasis
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2018-01-25 00:00:00 , DOI: 10.1021/acsinfecdis.7b00215 Haroon Mohammad 1 , Nehal H. Elghazawy 2 , Hassan E. Eldesouky 1 , Youssef A. Hegazy 1 , Waleed Younis 1 , Larisa Avrimova 3 , Tony Hazbun 3, 4 , Reem K. Arafa 2 , Mohamed N. Seleem 1, 5
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2018-01-25 00:00:00 , DOI: 10.1021/acsinfecdis.7b00215 Haroon Mohammad 1 , Nehal H. Elghazawy 2 , Hassan E. Eldesouky 1 , Youssef A. Hegazy 1 , Waleed Younis 1 , Larisa Avrimova 3 , Tony Hazbun 3, 4 , Reem K. Arafa 2 , Mohamed N. Seleem 1, 5
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Globally, invasive fungal infections pose a significant challenge to modern human medicine due to the limited number of antifungal drugs and the rise in resistance to current antifungal agents. A vast majority of invasive fungal infections are caused by species of Candida, Cryptococcus, and Aspergillus. Novel antifungal molecules consisting of unexploited chemical scaffolds with a unique mechanism are a pressing need. The present study identifies a dibromoquinoline compound (4b) with broad-spectrum antifungal activity that inhibits the growth of pertinent species of Candida (chiefly C. albicans), Cryptococcus, and Aspergillus at a concentration of as low as 0.5 μg/mL. Furthermore, 4b, at a subinhibitory concentration, interfered with the expression of two key virulence factors (hyphae and biofilm formation) involved in C. albicans pathogenesis. Three yeast deletion strains (cox17Δ, ssa1Δ, and aft2Δ) related to metal ion homeostasis were found to be highly sensitive to 4b in growth assays, indicating that the compound exerts its antifungal effect through a unique, previously unexploited mechanism. Supplementing the media with either copper or iron ions reversed the strain sensitivity to 4b, further corroborating that the compound targets metal ion homeostasis. 4b’s potent antifungal activity was validated in vivo, as the compound enhanced the survival of Caenorhabditis elegans infected with fluconazole-resistant C. albicans. The present study indicates that 4b warrants further investigation as a novel antifungal agent.
中文翻译：
新型二溴喹啉化合物具有针对金属离子稳态的有效抗真菌和抗毒活性的发现。
在全球范围内，由于抗真菌药物的数量有限以及对当前抗真菌药物的耐药性增加，侵袭性真菌感染对现代人类医学提出了重大挑战。绝大多数的侵袭性真菌感染是由念珠菌，隐球菌和曲霉菌引起的。迫切需要由具有独特机制的未开发化学支架组成的新型抗真菌分子。本研究确定了一种具有广谱抗真菌活性的二溴喹啉化合物（4b），该化合物可抑制念珠菌（主要为白色念珠菌），隐球菌和曲霉菌相关物种的生长。浓度低至0.5μg/ mL。此外，亚抑制浓度的4b干扰了白色念珠菌发病机理中两个关键毒力因子（菌丝和生物膜形成）的表达。在生长试验中，发现与金属离子稳态相关的三种酵母缺失菌株（cox17Δ，ssa1Δ和aft2Δ）对4b高度敏感，表明该化合物通过独特的，先前尚未利用的机制发挥其抗真菌作用。向介质中添加铜或铁离子可使应变敏感性降低至4b，进一步证实了该化合物的目标是金属离子稳态。4b其有效的抗真菌活性已在体内得到验证，因为该化合物可增强感染耐氟康唑的白色念珠菌感染的秀丽隐杆线虫的存活。本研究表明4b作为一种新型的抗真菌剂值得进一步研究。
更新日期：2018-01-25
中文翻译：
新型二溴喹啉化合物具有针对金属离子稳态的有效抗真菌和抗毒活性的发现。
在全球范围内，由于抗真菌药物的数量有限以及对当前抗真菌药物的耐药性增加，侵袭性真菌感染对现代人类医学提出了重大挑战。绝大多数的侵袭性真菌感染是由念珠菌，隐球菌和曲霉菌引起的。迫切需要由具有独特机制的未开发化学支架组成的新型抗真菌分子。本研究确定了一种具有广谱抗真菌活性的二溴喹啉化合物（4b），该化合物可抑制念珠菌（主要为白色念珠菌），隐球菌和曲霉菌相关物种的生长。浓度低至0.5μg/ mL。此外，亚抑制浓度的4b干扰了白色念珠菌发病机理中两个关键毒力因子（菌丝和生物膜形成）的表达。在生长试验中，发现与金属离子稳态相关的三种酵母缺失菌株（cox17Δ，ssa1Δ和aft2Δ）对4b高度敏感，表明该化合物通过独特的，先前尚未利用的机制发挥其抗真菌作用。向介质中添加铜或铁离子可使应变敏感性降低至4b，进一步证实了该化合物的目标是金属离子稳态。4b其有效的抗真菌活性已在体内得到验证，因为该化合物可增强感染耐氟康唑的白色念珠菌感染的秀丽隐杆线虫的存活。本研究表明4b作为一种新型的抗真菌剂值得进一步研究。
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