Department of Microbiology and Immunology, School of Medicine, University of Louisvillegrid.266623.5, Louisville, Kentucky, USA.
Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisvillegrid.266623.5, Louisville, Kentucky, USA.
Microbiol Spectr. 2021 Oct 31;9(2):e0095721. doi: 10.1128/Spectrum.00957-21. Epub 2021 Sep 8.
There is a rising global incidence of strains with high levels of resistance to fluconazole and other antifungal drugs, hence the need for novel antifungal treatment strategies. Here, we describe the first evidence of antifungal activity of Q-Griffithsin (Q-GRFT), a recombinant oxidation-resistant variant of Griffithsin, a marine red algal lectin with broad-spectrum antiviral activity. We demonstrated that Q-GRFT binds to α-mannan in the Candida albicans cell wall. We also observed that Q-GRFT binding disrupted cell wall integrity and induced reactive oxidative species (ROS) formation, resulting in cell death. Furthermore, we showed that Q-GRFT inhibited the growth of other species C. glabrata, C. parapsilosis, and C. krusei and had modest activity against some strains of multi- and pandrug-resistant C. auris. We found that Q-GRFT induced differential expression of numerous genes involved in response to cell stress, including those responsible for neutralizing ROS production and cell cycle regulation. In conclusion, this novel antifungal activity suggests that Q-GRFT is potentially an ideal drug candidate and represents an alternative strategy for the prevention and treatment of candidiasis. Fungal infections contribute to morbidity and mortality annually, and the number of organisms that are nonresponsive to the current available drug regimens are on the rise. There is a need to develop new agents to counter these infections and to add to the limited arsenal available to treat fungal infections. Our study has identified Q-GRFT, a broad-spectrum antiviral protein that harbors growth-inhibitory activity against several strains, as a potential candidate for the prevention and treatment of fungal infections.
全球范围内，对氟康唑和其他抗真菌药物高度耐药的菌株不断增加，因此需要新的抗真菌治疗策略。在这里，我们描述了 Q-Griffithsin（Q-GRFT）的抗真菌活性的第一个证据，Q-GRFT 是 Griffithsin 的一种重组氧化抗性变体，Griffithsin 是一种具有广谱抗病毒活性的海洋红藻凝集素。我们证明 Q-GRFT 与白色念珠菌细胞壁中的α-甘露聚糖结合。我们还观察到 Q-GRFT 结合破坏了细胞壁完整性并诱导活性氧（ROS）形成，导致细胞死亡。此外，我们表明 Q-GRFT 抑制了其他物种的生长，包括近平滑念珠菌、光滑念珠菌和克柔念珠菌，并且对一些多药耐药和泛耐药的 C. auris 菌株具有适度的活性。我们发现 Q-GRFT 诱导了参与细胞应激反应的许多基因的差异表达，包括那些负责中和 ROS 产生和细胞周期调节的基因。总之，这种新的抗真菌活性表明 Q-GRFT 可能是一种理想的药物候选物，并代表了预防和治疗念珠菌病的一种替代策略。真菌感染每年都会导致发病率和死亡率，并且对当前可用药物方案无反应的生物体数量正在增加。需要开发新的药物来对抗这些感染，并增加有限的治疗真菌感染的武器库。我们的研究已经确定了 Q-GRFT，一种广谱抗病毒蛋白，对几种 菌株具有生长抑制活性，作为预防和治疗真菌感染的潜在候选药物。
