Echinocandin Drugs Induce Differential Effects in Cytokinesis Progression and Cell Integrity
Fission yeast contains three essential β(1,3)-D-glucan synthases (GSs), Bgs1, Bgs3, and Bgs4, with non-overlapping roles in cell integrity and morphogenesis. Only the <i>bgs4<sup>+</sup></i> mutants <i>pbr1-8</i> and <i>pbr1-6</i> exhibit resistance to...
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MDPI AG
2021-12-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/12/1332 |
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| author | Natalia Yagüe Laura Gómez-Delgado M. Ángeles Curto Vanessa S. D. Carvalho M. Belén Moreno Pilar Pérez Juan Carlos Ribas Juan Carlos G. Cortés |
| author_facet | Natalia Yagüe Laura Gómez-Delgado M. Ángeles Curto Vanessa S. D. Carvalho M. Belén Moreno Pilar Pérez Juan Carlos Ribas Juan Carlos G. Cortés |
| author_sort | Natalia Yagüe |
| collection | DOAJ |
| description | Fission yeast contains three essential β(1,3)-D-glucan synthases (GSs), Bgs1, Bgs3, and Bgs4, with non-overlapping roles in cell integrity and morphogenesis. Only the <i>bgs4<sup>+</sup></i> mutants <i>pbr1-8</i> and <i>pbr1-6</i> exhibit resistance to GS inhibitors, even in the presence of the wild-type (WT) sequences of <i>bgs1<sup>+</sup></i> and <i>bgs3<sup>+</sup></i>. Thus, Bgs1 and Bgs3 functions seem to be unaffected by those GS inhibitors. To learn more about echinocandins’ mechanism of action and resistance, cytokinesis progression and cell death were examined by time-lapse fluorescence microscopy in WT and <i>pbr1-8</i> cells at the start of treatment with sublethal and lethal concentrations of anidulafungin, caspofungin, and micafungin. In WT, sublethal concentrations of the three drugs caused abundant cell death that was either suppressed (anidulafungin and micafungin) or greatly reduced (caspofungin) in <i>pbr1-8</i> cells. Interestingly, the lethal concentrations induced differential phenotypes depending on the echinocandin used. Anidulafungin and caspofungin were mostly fungistatic, heavily impairing cytokinesis progression in both WT and <i>pbr1-8</i>. As with sublethal concentrations, lethal concentrations of micafungin were primarily fungicidal in WT cells, causing cell lysis without impairing cytokinesis. The lytic phenotype was suppressed again in <i>pbr1-8</i> cells. Our results suggest that micafungin always exerts its fungicidal effect by solely inhibiting Bgs4. In contrast, lethal concentrations of anidulafungin and caspofungin cause an early cytokinesis arrest, probably by the combined inhibition of several GSs. |
| first_indexed | 2024-03-10T03:21:00Z |
| format | Article |
| id | doaj.art-f08b1c240eaf47f5bf1f3f8ecc446754 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T03:21:00Z |
| publishDate | 2021-12-01 |
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| series | Pharmaceuticals |
| spelling | doaj.art-f08b1c240eaf47f5bf1f3f8ecc4467542023-11-23T10:04:13ZengMDPI AGPharmaceuticals1424-82472021-12-011412133210.3390/ph14121332Echinocandin Drugs Induce Differential Effects in Cytokinesis Progression and Cell IntegrityNatalia Yagüe0Laura Gómez-Delgado1M. Ángeles Curto2Vanessa S. D. Carvalho3M. Belén Moreno4Pilar Pérez5Juan Carlos Ribas6Juan Carlos G. Cortés7Instituto de Biología Funcional y Genómica, Consejo Superior de Investigaciones Científicas (CSIC) and Universidad de Salamanca, 37007 Salamanca, SpainInstituto de Biología Funcional y Genómica, Consejo Superior de Investigaciones Científicas (CSIC) and Universidad de Salamanca, 37007 Salamanca, SpainInstituto de Biología Funcional y Genómica, Consejo Superior de Investigaciones Científicas (CSIC) and Universidad de Salamanca, 37007 Salamanca, SpainInstituto de Biología Funcional y Genómica, Consejo Superior de Investigaciones Científicas (CSIC) and Universidad de Salamanca, 37007 Salamanca, SpainInstituto de Biología Funcional y Genómica, Consejo Superior de Investigaciones Científicas (CSIC) and Universidad de Salamanca, 37007 Salamanca, SpainInstituto de Biología Funcional y Genómica, Consejo Superior de Investigaciones Científicas (CSIC) and Universidad de Salamanca, 37007 Salamanca, SpainInstituto de Biología Funcional y Genómica, Consejo Superior de Investigaciones Científicas (CSIC) and Universidad de Salamanca, 37007 Salamanca, SpainInstituto de Biología Funcional y Genómica, Consejo Superior de Investigaciones Científicas (CSIC) and Universidad de Salamanca, 37007 Salamanca, SpainFission yeast contains three essential β(1,3)-D-glucan synthases (GSs), Bgs1, Bgs3, and Bgs4, with non-overlapping roles in cell integrity and morphogenesis. Only the <i>bgs4<sup>+</sup></i> mutants <i>pbr1-8</i> and <i>pbr1-6</i> exhibit resistance to GS inhibitors, even in the presence of the wild-type (WT) sequences of <i>bgs1<sup>+</sup></i> and <i>bgs3<sup>+</sup></i>. Thus, Bgs1 and Bgs3 functions seem to be unaffected by those GS inhibitors. To learn more about echinocandins’ mechanism of action and resistance, cytokinesis progression and cell death were examined by time-lapse fluorescence microscopy in WT and <i>pbr1-8</i> cells at the start of treatment with sublethal and lethal concentrations of anidulafungin, caspofungin, and micafungin. In WT, sublethal concentrations of the three drugs caused abundant cell death that was either suppressed (anidulafungin and micafungin) or greatly reduced (caspofungin) in <i>pbr1-8</i> cells. Interestingly, the lethal concentrations induced differential phenotypes depending on the echinocandin used. Anidulafungin and caspofungin were mostly fungistatic, heavily impairing cytokinesis progression in both WT and <i>pbr1-8</i>. As with sublethal concentrations, lethal concentrations of micafungin were primarily fungicidal in WT cells, causing cell lysis without impairing cytokinesis. The lytic phenotype was suppressed again in <i>pbr1-8</i> cells. Our results suggest that micafungin always exerts its fungicidal effect by solely inhibiting Bgs4. In contrast, lethal concentrations of anidulafungin and caspofungin cause an early cytokinesis arrest, probably by the combined inhibition of several GSs.https://www.mdpi.com/1424-8247/14/12/1332fungiinvasive fungal infectionsfission yeastcell wallβ(1,3)-D-glucan synthaseantifungal drugs |
| spellingShingle | Natalia Yagüe Laura Gómez-Delgado M. Ángeles Curto Vanessa S. D. Carvalho M. Belén Moreno Pilar Pérez Juan Carlos Ribas Juan Carlos G. Cortés Echinocandin Drugs Induce Differential Effects in Cytokinesis Progression and Cell Integrity Pharmaceuticals fungi invasive fungal infections fission yeast cell wall β(1,3)-D-glucan synthase antifungal drugs |
| title | Echinocandin Drugs Induce Differential Effects in Cytokinesis Progression and Cell Integrity |
| title_full | Echinocandin Drugs Induce Differential Effects in Cytokinesis Progression and Cell Integrity |
| title_fullStr | Echinocandin Drugs Induce Differential Effects in Cytokinesis Progression and Cell Integrity |
| title_full_unstemmed | Echinocandin Drugs Induce Differential Effects in Cytokinesis Progression and Cell Integrity |
| title_short | Echinocandin Drugs Induce Differential Effects in Cytokinesis Progression and Cell Integrity |
| title_sort | echinocandin drugs induce differential effects in cytokinesis progression and cell integrity |
| topic | fungi invasive fungal infections fission yeast cell wall β(1,3)-D-glucan synthase antifungal drugs |
| url | https://www.mdpi.com/1424-8247/14/12/1332 |
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