Antifungal activity of eumelanin-inspired indoylenepheyleneethynylene against Cryptococcus neoformans.
Antifungal activity of eumelanin-inspired indoylenepheyleneethynylene against Cryptococcus neoformans.
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Eumelanin启发的Indoylenepheylethynynylene抗真菌活性针对Neoformans。
DOI：
10.3389/fmicb.2023.1339303
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发表时间：
2023
影响因子：
5.2
通讯作者：
中科院分区：
文献类型：
--
作者：
新型隐球菌是一种机会性真菌病原体，每年有152,000名免疫功能低下的人导致脑膜炎，每年导致112,000人死亡。现有的四类抗真菌药物靶向质膜甾醇（麦角甾醇）、核酸合成和细胞壁合成。现有的药物对隐球菌并不是很有效，抗真菌药物耐药性是一个日益严重的问题。合成了一种新的抗菌化合物，真黑素激发的吲哚炔乙炔，EIPE-1，对革兰氏阳性菌，包括耐甲氧西林金黄色葡萄球菌（MSRA）具有抗菌活性，但对革兰氏阴性菌没有抗菌活性。基于EIPE-1的抗菌活性，我们推测EIPE-1可能具有抗真菌活性。在这些研究中，我们测试了EIPE-1对新型隐球菌菌株H99和另外6种隐球菌临床分离株的作用。我们研究了EIPE-1的抗真菌活性、细胞毒性、对真菌基因表达的影响以及作用机制。结果表明，EIPE-1对7株隐球菌具有一定的杀真菌作用，mic值根据菌株的不同在1.56 ~ 3.125 μg/mL之间，且对哺乳动物细胞无毒。我们对暴露的细胞进行了扫描和透射电子显微镜，以检查EIPE-1治疗后生物体的结构变化。暴露的细胞显示出细胞壁和细胞膜的结构变化，内部内容物渗出细胞。为了了解EIPE-1对真菌基因表达的影响，我们进行了RNA测序。结果表明，EIPE-1影响应激反应、麦角甾醇生物合成、胶囊生物合成和细胞壁附着和重塑等过程。因此，我们的研究表明，EIPE-1对新生C.具有抗真菌活性，影响细胞结构和参与细胞膜稳定性和活力的多种真菌途径的基因表达。
Cryptococcus neoformans is an opportunistic fungal pathogen that causes meningitis in >152,000 immunocompromised individuals annually, leading to 112,000 yearly deaths. The four classes of existing antifungal agents target plasma membrane sterols (ergosterol), nucleic acid synthesis, and cell wall synthesis. Existing drugs are not highly effective against Cryptococcus, and antifungal drug resistance is an increasing problem. A novel antimicrobial compound, a eumelanin-inspired indoylenepheyleneethynylene, EIPE-1, was synthesized and has antimicrobial activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MSRA), but not towards Gram-negative organisms. Based on EIPE-1’s antibacterial activity, we hypothesized that EIPE-1 could have antifungal activity. For these studies, we tested EIPE-1 against C. neoformans strain H99 and 6 additional cryptococcal clinical isolates. We examined antifungal activity, cytotoxicity, effects on fungal gene expression, and mechanism of action of EIPE-1. Results showed that EIPE-1 has fungicidal effects on seven cryptococcal strains with MICs ranging from 1.56 to 3.125 μg/mL depending on the strain, and it is non-toxic to mammalian cells. We conducted scanning and transmission electron microscopy on the exposed cells to examine structural changes to the organism following EIPE-1 treatment. Cells exposed displayed structural changes to their cell wall and membranes, with internal contents leaking out of the cells. To understand the effect of EIPE-1 on fungal gene expression, RNA sequencing was conducted. Results showed that EIPE-1 affects several processes involved stress response, ergosterol biosynthesis, capsule biosynthesis, and cell wall attachment and remodeling. Therefore, our studies demonstrate that EIPE-1 has antifungal activity against C. neoformans, which affects both cellular structure and gene expression of multiple fungal pathways involved in cell membrane stability and viability.
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影响因子：
4.6
作者：
Nelson BN;Beakley SG;Posey S;Conn B;Maritz E;Seshu J;Wozniak KL
通讯作者：
Wozniak KL
影响因子：
5.7
作者：
Danchik C;Casadevall A
通讯作者：
Casadevall A
影响因子：
3.4
作者：
Coelho C;Casadevall A
通讯作者：
Casadevall A
影响因子：
9.4
作者：
Espinel-Ingroff, A;Chaturvedi, V;Rinaldi, MG
通讯作者：
Rinaldi, MG
影响因子：
0.8
作者：
Dhana, Ashar
通讯作者：
Dhana, Ashar