liriodenine对新型隐球菌和加蒂隐球菌复合体临床菌株的抑菌活性。

IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Accounts of Chemical Research Pub Date : 2022-09-05 eCollection Date: 2022-01-01 DOI:10.1590/1678-9199-JVATITD-2022-0006
Adriele Dandara Levorato-Vinche, Marcia de Souza Carvalho Melhem, Lucas Xavier Bonfietti, Iván de-la-Cruz-Chacón, Carmen Sílvia Fernandes Boaro, Alexandre Todorovic Fabro, Gisela Ferreira, Julhiany de Fátima da Silva, Daniela Carvalho Dos Santos, Beatriz Aparecida Soares Pereira, Camila Marçon, Lariza Maza, Lídia Raquel de Carvalho, Rinaldo Poncio Mendes
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引用次数: 1

摘要

背景:隐球菌性脑膜炎在艾滋病患者中的发病率仍然很高。治疗的选择是氟胞嘧啶(5-FC)与两性霉素B脱氧胆酸酯(AmBd)或其脂质制剂的协同组合。然而,许多国家没有5-FC,而AmB要求住院治疗。AmB与抑菌剂氟康唑(FLC)联合使用或单独使用高剂量FLC每日成为选择。然而,FLC单药治疗延迟了脑脊液的灭菌,主要是真菌负担高。这些发现表明需要寻找新的抗真菌化合物,如利riodenine。方法:采用EUCAST方法,以两性霉素B脱氧胆酸为对照,测定Liriodenine对30株新型隐球菌(C. neoformans)复合体和30株加蒂隐球菌(C. gattii)复合体的最低抑菌浓度(MIC),通过3种方法评价Liriodenine的抑菌活性;对两株新生梭菌复合体和一株加蒂梭菌复合体进行时间杀伤方法研究;和隐球菌细胞损伤,通过透射电子显微镜(TEM)评估。Liriodenine在0.75和1.50 mg时的吸收和安全性。在BALB/c小鼠中评估kg-1剂量。结果:Liriodenine mic范围为3.9 ~ 62.5 μg。两种复合物均为mL-1,两者之间无差异。时间杀伤方法证实了其浓度依赖性的杀真菌效果,在liriodenine最高浓度(32倍MIC)下杀死所有低于检测限(33 CFU.mL-1)的菌株,并在前48小时内具有优势活性。Liriodenine诱导了严重的隐球菌改变-细胞质有强烈的稀薄和/或降解,细胞器损伤和液泡的存在。Liriodenine在较低剂量下吸收较好,消化道无组织病理学改变。结论:时间杀伤法证实的杀真菌活性、透射电镜观察到的强烈隐球菌损伤、灌药后的吸收和试验剂量下的安全性表明,利riodenine分子是一种有前景的抗隐球菌药物先导物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Antifungal activity of liriodenine on clinical strains of <i>Cryptococcus neoformans</i> and <i>Cryptococcus gattii</i> species complexes.

Antifungal activity of liriodenine on clinical strains of <i>Cryptococcus neoformans</i> and <i>Cryptococcus gattii</i> species complexes.

Antifungal activity of liriodenine on clinical strains of <i>Cryptococcus neoformans</i> and <i>Cryptococcus gattii</i> species complexes.

Antifungal activity of liriodenine on clinical strains of Cryptococcus neoformans and Cryptococcus gattii species complexes.

Background: Cryptoccocal meningitis continues to present high incidence among AIDS patients. The treatment of choice is the synergistic combination of flucytosine (5-FC) with amphotericin B deoxycholate (AmBd) or its lipid formulations. However, 5-FC is unavailable in many countries and AmB demands hospitalization. The combination of AmB with the fungistatic fluconazole (FLC) or the use of high FLC daily doses alone became the choice. Nonetheless, sterilization of cerebrospinal fluid is delayed with FLC monotherapy, mainly with high fungal burden. These findings suggest the search for new antifungal compounds, such as liriodenine.

Methods: Liriodenine antifungal activity was evaluated by three procedures: determining the minimum inhibitory concentration (MIC) on 30 strains of the Cryptococcus neoformans (C. neoformans) complex and 30 of the Cryptococcus gattii (C. gattii) complex, using EUCAST methodology and amphotericin B deoxycholate as control; performing the time-kill methodology in two strains of the C. neoformans complex and one of the C. gattii complex; and injury to cryptococcal cells, evaluated by transmission electron microscopy (TEM). Liriodenine absorption and safety at 0.75 and 1.50 mg.kg-1 doses were evaluated in BALB/c mice.

Results: Liriodenine MICs ranged from 3.9 to 62.5 μg.mL-1 for both species complexes, with no differences between them. Time-kill methodology confirmed its concentration-dependent fungicidal effect, killing all the strains below the limit of detection (33 CFU.mL-1) at the highest liriodenine concentration (32-fold MIC), with predominant activity during the first 48 hours. Liriodenine induced severe Cryptococcus alterations - cytoplasm with intense rarefaction and/or degradation, injury of organelles, and presence of vacuoles. Liriodenine was better absorbed at lower doses, with no histopathological alterations on the digestive tract.

Conclusion: The fungicidal activity confirmed by time-kill methodology, the intense Cryptococcus injury observed by TEM, the absorption after gavage administration, and the safety at the tested doses indicate that the liriodenine molecule is a promising drug lead for development of anticryptococcal agents.

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来源期刊
Accounts of Chemical Research
Accounts of Chemical Research 化学-化学综合
CiteScore
31.40
自引率
1.10%
发文量
312
审稿时长
2 months
期刊介绍: Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.
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