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 1.8 3区 医学 Q4 TOXICOLOGY
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
{"title":"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。","authors":"Adriele Dandara Levorato-Vinche,&nbsp;Marcia de Souza Carvalho Melhem,&nbsp;Lucas Xavier Bonfietti,&nbsp;Iván de-la-Cruz-Chacón,&nbsp;Carmen Sílvia Fernandes Boaro,&nbsp;Alexandre Todorovic Fabro,&nbsp;Gisela Ferreira,&nbsp;Julhiany de Fátima da Silva,&nbsp;Daniela Carvalho Dos Santos,&nbsp;Beatriz Aparecida Soares Pereira,&nbsp;Camila Marçon,&nbsp;Lariza Maza,&nbsp;Lídia Raquel de Carvalho,&nbsp;Rinaldo Poncio Mendes","doi":"10.1590/1678-9199-JVATITD-2022-0006","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>Liriodenine antifungal activity was evaluated by three procedures: determining the minimum inhibitory concentration (MIC) on 30 strains of the <i>Cryptococcus neoformans</i> (<i>C. neoformans</i>) complex and 30 of the <i>Cryptococcus gattii</i> (<i>C. gattii</i>) complex, using EUCAST methodology and amphotericin B deoxycholate as control; performing the time-kill methodology in two strains of the <i>C. neoformans</i> complex and one of the <i>C. gattii</i> complex; and injury to cryptococcal cells, evaluated by transmission electron microscopy (TEM). Liriodenine absorption and safety at 0.75 and 1.50 mg.kg<sup>-1</sup> doses were evaluated in BALB/c mice.</p><p><strong>Results: </strong>Liriodenine MICs ranged from 3.9 to 62.5 μg.mL<sup>-1</sup> 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<sup>-1</sup>) at the highest liriodenine concentration (32-fold MIC), with predominant activity during the first 48 hours. Liriodenine induced severe <i>Cryptococcus</i> 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.</p><p><strong>Conclusion: </strong>The fungicidal activity confirmed by time-kill methodology, the intense <i>Cryptococcus</i> 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.</p>","PeriodicalId":17565,"journal":{"name":"Journal of Venomous Animals and Toxins Including Tropical Diseases","volume":null,"pages":null},"PeriodicalIF":1.8000,"publicationDate":"2022-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9469771/pdf/","citationCount":"1","resultStr":"{\"title\":\"Antifungal activity of liriodenine on clinical strains of <i>Cryptococcus neoformans</i> and <i>Cryptococcus gattii</i> species complexes.\",\"authors\":\"Adriele Dandara Levorato-Vinche,&nbsp;Marcia de Souza Carvalho Melhem,&nbsp;Lucas Xavier Bonfietti,&nbsp;Iván de-la-Cruz-Chacón,&nbsp;Carmen Sílvia Fernandes Boaro,&nbsp;Alexandre Todorovic Fabro,&nbsp;Gisela Ferreira,&nbsp;Julhiany de Fátima da Silva,&nbsp;Daniela Carvalho Dos Santos,&nbsp;Beatriz Aparecida Soares Pereira,&nbsp;Camila Marçon,&nbsp;Lariza Maza,&nbsp;Lídia Raquel de Carvalho,&nbsp;Rinaldo Poncio Mendes\",\"doi\":\"10.1590/1678-9199-JVATITD-2022-0006\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>Liriodenine antifungal activity was evaluated by three procedures: determining the minimum inhibitory concentration (MIC) on 30 strains of the <i>Cryptococcus neoformans</i> (<i>C. neoformans</i>) complex and 30 of the <i>Cryptococcus gattii</i> (<i>C. gattii</i>) complex, using EUCAST methodology and amphotericin B deoxycholate as control; performing the time-kill methodology in two strains of the <i>C. neoformans</i> complex and one of the <i>C. gattii</i> complex; and injury to cryptococcal cells, evaluated by transmission electron microscopy (TEM). Liriodenine absorption and safety at 0.75 and 1.50 mg.kg<sup>-1</sup> doses were evaluated in BALB/c mice.</p><p><strong>Results: </strong>Liriodenine MICs ranged from 3.9 to 62.5 μg.mL<sup>-1</sup> 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<sup>-1</sup>) at the highest liriodenine concentration (32-fold MIC), with predominant activity during the first 48 hours. Liriodenine induced severe <i>Cryptococcus</i> 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.</p><p><strong>Conclusion: </strong>The fungicidal activity confirmed by time-kill methodology, the intense <i>Cryptococcus</i> 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.</p>\",\"PeriodicalId\":17565,\"journal\":{\"name\":\"Journal of Venomous Animals and Toxins Including Tropical Diseases\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.8000,\"publicationDate\":\"2022-09-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9469771/pdf/\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Venomous Animals and Toxins Including Tropical Diseases\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1590/1678-9199-JVATITD-2022-0006\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2022/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q4\",\"JCRName\":\"TOXICOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Venomous Animals and Toxins Including Tropical Diseases","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1590/1678-9199-JVATITD-2022-0006","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2022/1/1 0:00:00","PubModel":"eCollection","JCR":"Q4","JCRName":"TOXICOLOGY","Score":null,"Total":0}
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.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
4.80
自引率
8.30%
发文量
39
审稿时长
6-12 weeks
期刊介绍: Journal of Venomous Animals and Toxins including Tropical Diseases (JVATiTD) is a non-commercial academic open access publication dedicated to research on all aspects of toxinology, venomous animals and tropical diseases. Its interdisciplinary content includes original scientific articles covering research on toxins derived from animals, plants and microorganisms. Topics of interest include, but are not limited to:systematics and morphology of venomous animals;physiology, biochemistry, pharmacology and immunology of toxins;epidemiology, clinical aspects and treatment of envenoming by different animals, plants and microorganisms;development and evaluation of antivenoms and toxin-derivative products;epidemiology, clinical aspects and treatment of tropical diseases (caused by virus, bacteria, algae, fungi and parasites) including the neglected tropical diseases (NTDs) defined by the World Health Organization.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信