Nayak Anushka, Chavarria Alejandro, Sanders Kyla N, Ghalei Homa, Khoshnevis Sohail
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA.
bioRxiv. 2023 Oct 15:2023.10.12.562127. doi: 10.1101/2023.10.12.562127.
, an opportunistic fungal human pathogen, is a major threat to the healthcare system due to both infections in immunocompromised individuals and the emergence of antifungal resistance. Fungal infection caused by , candidiasis, is a life-threatening condition in immunocompromised patients and the current treatments are mostly restricted to polyenes, azoles, and echinocandins. Use of these antifungals is limited by toxicity, drug-drug interactions, and the emergence of resistance, underscoring the importance of identifying novel therapeutic targets and the need for new treatment approaches. can undergo a morphological transition from yeast to hyphae and this transition is central to virulence. Here, we determine the impact of sinefungin, a natural nucleoside analog of S-adenosyl methionine, on the virulence of strain SC5314 by evaluating treatment effects on the morphological transition, human epithelial cell adhesion, and biofilm formation. Our data indicate that sinefungin impairs pathogenic traits of including hyphal lengthening, biofilm formation and the adhesion to the human epithelial cell lines, without adversely affecting human cells, therefore highlighting sinefungin as a potential avenue for therapeutic intervention. We determine that the formation of N6-methyladenosine (mA) is particularly disturbed by sinefungin. More broadly, this study underscores the importance of considering the post-transcriptional control mechanisms of pathogenicity when designing therapeutic solutions to fungal infection.
白色念珠菌是一种机会性人类真菌病原体，由于其在免疫功能低下个体中的感染以及抗真菌耐药性的出现，对医疗系统构成了重大威胁。由白色念珠菌引起的真菌感染，即念珠菌病，在免疫功能低下的患者中是一种危及生命的疾病，目前的治疗方法大多局限于多烯类、唑类和棘白菌素类。这些抗真菌药物的使用受到毒性、药物相互作用和耐药性出现的限制，这凸显了识别新治疗靶点的重要性以及对新治疗方法的需求。白色念珠菌可以经历从酵母形态到菌丝形态的转变，这种转变是其致病性的核心。在这里，我们通过评估对形态转变、人上皮细胞黏附及生物膜形成的治疗效果，确定了S -腺苷甲硫氨酸的天然核苷类似物西奈芬净对白色念珠菌菌株SC5314毒力的影响。我们的数据表明，西奈芬净损害了白色念珠菌的致病特性，包括菌丝伸长、生物膜形成以及对人上皮细胞系的黏附，而不会对人体细胞产生不利影响，因此突出了西奈芬净作为一种潜在治疗干预途径的地位。我们确定N6 -甲基腺苷（mA）的形成尤其受到西奈芬净的干扰。更广泛地说，这项研究强调了在设计真菌感染治疗方案时考虑致病性转录后控制机制的重要性。
