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, 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","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":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"e20220006"},"PeriodicalIF":16.4000,"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, 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\",\"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\":1,\"journal\":{\"name\":\"Accounts of Chemical Research\",\"volume\":\" \",\"pages\":\"e20220006\"},\"PeriodicalIF\":16.4000,\"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\":\"Accounts of Chemical Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1590/1678-9199-JVATITD-2022-0006\",\"RegionNum\":1,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2022/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Accounts of Chemical Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1590/1678-9199-JVATITD-2022-0006","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2022/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
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.
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.