Laboratorio de Estudos Avancados de Microrganismos Emergentes e Resistentes, Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Goes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Programa de Pós-Graduação em Bioquímica, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Curr Top Med Chem. 2019;19(28):2527-2553. doi: 10.2174/1568026619666191025152412.
Fungal infections are a veritable public health problem worldwide. The increasing number of patient populations at risk (e.g. transplanted individuals, cancer patients, and HIV-infected people), as well as the use of antifungal agents for prophylaxis in medicine, have favored the emergence of previously rare or newly identified fungal species. Indeed, novel antifungal resistance patterns have been observed, including environmental sources and the emergence of simultaneous resistance to different antifungal classes, especially in Candida spp., which are known for the multidrug-resistance (MDR) profile. In order to circumvent this alarming scenario, the international researchers' community is engaged in discovering new, potent, and promising compounds to be used in a near future to treat resistant fungal infections in hospital settings on a global scale. In this context, many compounds with antifungal action from both natural and synthetic sources are currently under clinical development, including those that target either ergosterol or β(1,3)-D-glucan, presenting clear evidence of pharmacologic/pharmacokinetic advantages over currently available drugs against these two well-known fungal target structures. Among these are the tetrazoles VT-1129, VT-1161, and VT-1598, the echinocandin CD101, and the glucan synthase inhibitor SCY-078. In this review, we compiled the most recent antifungal compounds that are currently in clinical trials of development and described the potential outcomes against emerging and rare Candida species, with a focus on C. auris, C. dubliniensis, C. glabrata, C. guilliermondii, C. haemulonii, and C. rugosa. In addition to possibly overcoming the limitations of currently available antifungals, new investigational chemical agents that can enhance the classic antifungal activity, thereby reversing previously resistant phenotypes, were also highlighted. While novel and increasingly MDR non-albicans Candida species continue to emerge worldwide, novel strategies for rapid identification and treatment are needed to combat these life-threatening opportunistic fungal infections.
真菌感染是全球真正的公共卫生问题。越来越多的高危人群（如移植患者、癌症患者和 HIV 感染者）以及在医学中预防性使用抗真菌药物，都有利于以前罕见或新发现的真菌物种的出现。事实上，已经观察到新的抗真菌耐药模式，包括环境来源和同时对不同抗真菌类别的耐药性，特别是在念珠菌属中，该菌以多药耐药（MDR）表型而闻名。为了避免这种令人担忧的情况，国际研究人员社区正在致力于发现新的、有效且有前途的化合物，以便在不久的将来在全球范围内用于治疗医院环境中耐药的真菌感染。在这种情况下，许多具有抗真菌作用的天然和合成来源的化合物目前正在临床开发中，包括针对麦角固醇或β(1,3)-D-葡聚糖的化合物，它们在药效学/药代动力学方面明显优于目前针对这两种知名真菌靶结构的现有药物。其中包括唑类 VT-1129、VT-1161 和 VT-1598、棘白菌素 CD101 和葡聚糖合酶抑制剂 SCY-078。在这篇综述中，我们汇集了目前处于临床试验开发阶段的最新抗真菌化合物，并描述了它们对新兴和罕见念珠菌属的潜在疗效，重点是耳念珠菌、都柏林念珠菌、光滑念珠菌、近平滑念珠菌、吉利蒙念珠菌和罗鲁氏念珠菌。除了可能克服现有抗真菌药物的局限性外，还强调了新的研究性化学药物可以增强经典抗真菌活性，从而逆转以前的耐药表型。随着新型且越来越多的 MDR 非白念珠菌属念珠菌在全球范围内不断出现，需要新的快速鉴定和治疗策略来对抗这些危及生命的机会性真菌感染。
