Ogundeji Adepemi O, Pohl Carolina H, Sebolai Olihile M
Department of Microbial, Biochemical and Food Biotechnology, University of the Free State, Bloemfontein, South Africa.
Department of Microbial, Biochemical and Food Biotechnology, University of the Free State, Bloemfontein, South Africa
Antimicrob Agents Chemother. 2016 Jul 22;60(8):4799-808. doi: 10.1128/AAC.02810-15. Print 2016 Aug.
The usage of fluconazole and amphotericin B in clinical settings is often limited by, among other things, drug resistance development and undesired side effects. Thus, there is a constant need to find new drugs to better manage fungal infections. Toward this end, the study described in this paper considered the repurposing of aspirin (acetylsalicylic acid) and ibuprofen as alternative drugs to control the growth of cryptococcal cells. In vitro susceptibility tests, including a checkerboard assay, were performed to assess the response of Cryptococcus neoformans and Cryptococcus gattii to the above-mentioned anti-inflammatory drugs. Next, the capacity of these two drugs to induce stress as well as their mode of action in the killing of cryptococcal cells was determined. The studied fungal strains revealed a response to both aspirin and ibuprofen that was dose dependent, with ibuprofen exerting greater antimicrobial action. More importantly, the MICs of these drugs did not negatively (i) affect growth or (ii) impair the functioning of macrophages; rather, they enhanced the ability of these immune cells to phagocytose cryptococcal cells. Ibuprofen was also shown to act in synergy with fluconazole and amphotericin B. The treatment of cryptococcal cells with aspirin or ibuprofen led to stress induction via activation of the high-osmolarity glycerol (HOG) pathway, and cell death was eventually achieved through reactive oxygen species (ROS)-mediated membrane damage. The presented data highlight the potential clinical application of aspirin and ibuprofen as candidate anti-Cryptococcus drugs.
在临床环境中，氟康唑和两性霉素B的使用常常受到多种因素的限制，其中包括耐药性的产生和不良副作用。因此，一直需要寻找新的药物来更好地治疗真菌感染。为此，本文所述的研究考虑将阿司匹林（乙酰水杨酸）和布洛芬重新用作控制隐球菌细胞生长的替代药物。进行了包括棋盘法在内的体外药敏试验，以评估新型隐球菌和格特隐球菌对上述抗炎药物的反应。接下来，确定了这两种药物诱导应激的能力及其杀死隐球菌细胞的作用方式。所研究的真菌菌株对阿司匹林和布洛芬均呈现剂量依赖性反应，其中布洛芬具有更强的抗菌作用。更重要的是，这些药物的最低抑菌浓度并未对（i）生长产生负面影响，也未（ii）损害巨噬细胞的功能；相反，它们增强了这些免疫细胞吞噬隐球菌细胞的能力。布洛芬还显示出与氟康唑和两性霉素B具有协同作用。用阿司匹林或布洛芬处理隐球菌细胞会通过激活高渗甘油（HOG）途径诱导应激，最终通过活性氧（ROS）介导的膜损伤实现细胞死亡。所呈现的数据突出了阿司匹林和布洛芬作为候选抗隐球菌药物的潜在临床应用价值。
