Sousa Naira Sulany Oliveira de, Almeida Juan Diego Ribeiro de, Rocha Linnek Silva da, Moreira Izabela de Mesquita Bárcia, Fernandes Flávia da Silva, Matsuura Ani Beatriz Jackisch, Cruz Kátia Santana, Lima Emersom Silva, Souza Érica Simplício de, Frickmann Hagen, Souza João Vicente Braga de
Program in Biodiversity and Biotechnology of the Bionorte Network (PPG-BIONORTE), Amazonas State University (UEA), Manaus 69065-001, AM, Brazil.
Mycology Laboratory, National Institute for Amazonian Research (INPA), Manaus 69067-375, AM, Brazil.
Antibiotics (Basel). 2025 Jun 13;14(6):602. doi: 10.3390/antibiotics14060602.
Cryptococcosis, caused by and species complexes, remains a significant health concern, particularly among immunocompromised patients. The emergence of antifungal resistance and toxicity of conventional treatment underscore the urgent need for novel therapeutic approaches. Combination therapies represent a promising strategy to enhance efficacy and overcome resistance. This study investigated the antifungal activity of five naphthoquinones against nine isolates of spp. and assessed their synergistic effects with amphotericin B (AmB). : In this study, five selected naphthoquinones were evaluated for their antifungal activity against spp. isolates using broth microdilution assays to determine minimum inhibitory concentrations (MICs), according to CLSI guidelines. The potential synergistic effect with AmB was assessed using checkerboard assays, with synergy interpreted based on the fractional inhibitory concentration index (FICI). Cytotoxicity was evaluated in MRC-5 human lung fibroblast cells using the MTT assay. : Among the compounds tested, 2-methoxynaphthalene-1,4-dione (2-MNQ) demonstrated antifungal activity, with MIC values ranging from 3.12 to 12.5 µg/mL. Checkerboard assays revealed a synergistic interaction between 2-MNQ and AmB, with a fractional inhibitory concentration index (FICI) of 0.27. The combination reduced the MIC of AmB by 4.17-fold. These findings highlight the potential of synthetic naphthoquinones, particularly 2-MNQ, as effective antifungal agents with synergistic properties when combined with AmB. The observed synergy suggests complementary mechanisms, including increased fungal membrane permeability and oxidative stress induction. : This study highlights the potential of 2-MNQ and 2,3-DBNQ as antifungal candidates against spp., with emphasis on the synergistic interaction observed between 2-MNQ and amphotericin B. The findings reinforce the importance of structural modifications in naphthoquinones to enhance antifungal activity and support the need for further preclinical studies investigating combination therapies aimed at improving treatment efficacy in patients with cryptococcosis.
由新型隐球菌复合体引起的隐球菌病仍然是一个重大的健康问题，尤其是在免疫功能低下的患者中。抗真菌耐药性的出现以及传统治疗的毒性凸显了对新型治疗方法的迫切需求。联合疗法是提高疗效和克服耐药性的一种有前景的策略。本研究调查了五种萘醌对9株新型隐球菌分离株的抗真菌活性，并评估了它们与两性霉素B（AmB）的协同作用。：在本研究中，根据美国临床和实验室标准协会（CLSI）指南，使用肉汤微量稀释法测定最低抑菌浓度（MIC），评估了五种选定的萘醌对新型隐球菌分离株的抗真菌活性。使用棋盘法评估与AmB的潜在协同作用，并根据分数抑菌浓度指数（FICI）解释协同作用。使用MTT法在MRC-5人肺成纤维细胞中评估细胞毒性。：在所测试的化合物中，2-甲氧基萘-1,4-二酮（2-MNQ）表现出抗真菌活性，MIC值范围为3.12至12.5μg/mL。棋盘法显示2-MNQ与AmB之间存在协同相互作用，分数抑菌浓度指数（FICI）为0.27。该组合使AmB的MIC降低了4.17倍。这些发现突出了合成萘醌，特别是2-MNQ，作为与AmB联合时具有协同特性的有效抗真菌剂的潜力。观察到的协同作用表明存在互补机制，包括增加真菌细胞膜通透性和诱导氧化应激。：本研究突出了2-MNQ和2,3-DBNQ作为抗新型隐球菌候选药物的潜力，重点是观察到的2-MNQ与两性霉素B之间的协同相互作用。这些发现强化了萘醌结构修饰对增强抗真菌活性的重要性，并支持需要进一步进行临床前研究，以调查旨在提高隐球菌病患者治疗疗效的联合疗法。
