Scorzoni Liliana, de Paula E Silva Ana C A, Marcos Caroline M, Assato Patrícia A, de Melo Wanessa C M A, de Oliveira Haroldo C, Costa-Orlandi Caroline B, Mendes-Giannini Maria J S, Fusco-Almeida Ana M
Laboratório de Micologia Clínica, Departamento de Análises Clínicas, Universidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas Araraquara, Brasil.
Front Microbiol. 2017 Jan 23;8:36. doi: 10.3389/fmicb.2017.00036. eCollection 2017.
The high rates of morbidity and mortality caused by fungal infections are associated with the current limited antifungal arsenal and the high toxicity of the compounds. Additionally, identifying novel drug targets is challenging because there are many similarities between fungal and human cells. The most common antifungal targets include fungal RNA synthesis and cell wall and membrane components, though new antifungal targets are being investigated. Nonetheless, fungi have developed resistance mechanisms, such as overexpression of efflux pump proteins and biofilm formation, emphasizing the importance of understanding these mechanisms. To address these problems, different approaches to preventing and treating fungal diseases are described in this review, with a focus on the resistance mechanisms of fungi, with the goal of developing efficient strategies to overcoming and preventing resistance as well as new advances in antifungal therapy. Due to the limited antifungal arsenal, researchers have sought to improve treatment via different approaches, and the synergistic effect obtained by the combination of antifungals contributes to reducing toxicity and could be an alternative for treatment. Another important issue is the development of new formulations for antifungal agents, and interest in nanoparticles as new types of carriers of antifungal drugs has increased. In addition, modifications to the chemical structures of traditional antifungals have improved their activity and pharmacokinetic parameters. Moreover, a different approach to preventing and treating fungal diseases is immunotherapy, which involves different mechanisms, such as vaccines, activation of the immune response and inducing the production of host antimicrobial molecules. Finally, the use of a mini-host has been encouraging for testing because these animal models demonstrate a good correlation with the mammalian model; they also increase the speediness of as well as facilitate the preliminary testing of new antifungal agents. In general, many years are required from discovery of a new antifungal to clinical use. However, the development of new antifungal strategies will reduce the therapeutic time and/or increase the quality of life of patients.
真菌感染导致的高发病率和死亡率与当前有限的抗真菌药物库以及这些化合物的高毒性有关。此外,识别新的药物靶点具有挑战性,因为真菌细胞和人类细胞之间存在许多相似之处。最常见的抗真菌靶点包括真菌RNA合成以及细胞壁和细胞膜成分,不过新的抗真菌靶点正在研究中。尽管如此,真菌已经形成了耐药机制,如外排泵蛋白的过度表达和生物膜形成,这凸显了理解这些机制的重要性。为了解决这些问题,本综述描述了预防和治疗真菌疾病的不同方法,重点是真菌的耐药机制,目标是制定有效的策略来克服和预防耐药性以及抗真菌治疗的新进展。由于抗真菌药物库有限,研究人员试图通过不同方法改善治疗,抗真菌药物联合使用所产生的协同效应有助于降低毒性,可能成为一种治疗选择。另一个重要问题是抗真菌药物新剂型的开发,对抗真菌药物新型载体纳米颗粒的兴趣有所增加。此外,对传统抗真菌药物化学结构的修饰改善了它们的活性和药代动力学参数。此外,预防和治疗真菌疾病的另一种方法是免疫疗法,它涉及不同机制,如疫苗、激活免疫反应和诱导宿主抗菌分子的产生。最后,使用小型宿主进行测试很有前景,因为这些动物模型与哺乳动物模型具有良好的相关性;它们还提高了新抗真菌药物初步测试的速度并使其更加便利。一般来说,从发现一种新的抗真菌药物到临床应用需要很多年。然而,新抗真菌策略的发展将缩短治疗时间和/或提高患者的生活质量。