Cell wall perturbation sensitizes fungi to the antimalarial drug chloroquine
Chloroquine (CQ) has been a mainstay of antimalarial drug treatment for several decades. Additional therapeutic actions of CQ have been described, including some reports of fungal inhibition. Here we investigated the action of CQ in fungi, including the yeast model Saccharomyces cerevisiae. A genome...
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| Format: | Article |
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American Society for Microbiology
2013
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| Online Access: | https://eprints.nottingham.ac.uk/2343/ |
| _version_ | 1848790760431812608 |
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| author | Islahudin, Farida Khozoie, Combiz Bates, Steven Ting, Kang-Nee Pleass, Richard J. Avery, Simon V. |
| author_facet | Islahudin, Farida Khozoie, Combiz Bates, Steven Ting, Kang-Nee Pleass, Richard J. Avery, Simon V. |
| author_sort | Islahudin, Farida |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Chloroquine (CQ) has been a mainstay of antimalarial drug treatment for several decades. Additional therapeutic actions of CQ have been described, including some reports of fungal inhibition. Here we investigated the action of CQ in fungi, including the yeast model Saccharomyces cerevisiae. A genomewide yeast deletion strain collection was screened against CQ, revealing that bck1Δ and slt2Δ mutants of the cell wall integrity pathway are CQ hypersensitive. This phenotype was rescued with sorbitol, consistent with cell wall involvement. The cell wall-targeting agent caffeine caused hypersensitivity to CQ, as did cell wall perturbation by sonication. The phenotypes were not caused by CQ-induced changes to cell wall components. Instead, CQ accumulated to higher levels in cells with perturbed cell walls: CQ uptake was 2- to 3-fold greater in bck1Δ and slt2Δ mutants than in wild-type yeast. CQ toxicity was synergistic with that of the major cell wall-targeting antifungal drug, caspofungin. The MIC of caspofungin against the yeast pathogen Candida albicans was decreased 2-fold by 250 μM CQ and up to 8-fold at higher CQ concentrations. Similar effects were seen in Candida glabrata and Aspergillus fumigatus. The results show that the cell wall is critical for CQ resistance in fungi and suggest that combination treatments with cell wall-targeting drugs could have potential for antifungal treatment. |
| first_indexed | 2025-11-14T18:17:44Z |
| format | Article |
| id | nottingham-2343 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T18:17:44Z |
| publishDate | 2013 |
| publisher | American Society for Microbiology |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-23432020-05-04T20:18:59Z https://eprints.nottingham.ac.uk/2343/ Cell wall perturbation sensitizes fungi to the antimalarial drug chloroquine Islahudin, Farida Khozoie, Combiz Bates, Steven Ting, Kang-Nee Pleass, Richard J. Avery, Simon V. Chloroquine (CQ) has been a mainstay of antimalarial drug treatment for several decades. Additional therapeutic actions of CQ have been described, including some reports of fungal inhibition. Here we investigated the action of CQ in fungi, including the yeast model Saccharomyces cerevisiae. A genomewide yeast deletion strain collection was screened against CQ, revealing that bck1Δ and slt2Δ mutants of the cell wall integrity pathway are CQ hypersensitive. This phenotype was rescued with sorbitol, consistent with cell wall involvement. The cell wall-targeting agent caffeine caused hypersensitivity to CQ, as did cell wall perturbation by sonication. The phenotypes were not caused by CQ-induced changes to cell wall components. Instead, CQ accumulated to higher levels in cells with perturbed cell walls: CQ uptake was 2- to 3-fold greater in bck1Δ and slt2Δ mutants than in wild-type yeast. CQ toxicity was synergistic with that of the major cell wall-targeting antifungal drug, caspofungin. The MIC of caspofungin against the yeast pathogen Candida albicans was decreased 2-fold by 250 μM CQ and up to 8-fold at higher CQ concentrations. Similar effects were seen in Candida glabrata and Aspergillus fumigatus. The results show that the cell wall is critical for CQ resistance in fungi and suggest that combination treatments with cell wall-targeting drugs could have potential for antifungal treatment. American Society for Microbiology 2013-08 Article PeerReviewed Islahudin, Farida, Khozoie, Combiz, Bates, Steven, Ting, Kang-Nee, Pleass, Richard J. and Avery, Simon V. (2013) Cell wall perturbation sensitizes fungi to the antimalarial drug chloroquine. Antimicrobial Agents and Chemotherapy, 57 (8). pp. 3889-3896. ISSN 0066-4804 http://aac.asm.org/content/57/8/3889.full doi:10.1128/AAC.00478-13 doi:10.1128/AAC.00478-13 |
| spellingShingle | Islahudin, Farida Khozoie, Combiz Bates, Steven Ting, Kang-Nee Pleass, Richard J. Avery, Simon V. Cell wall perturbation sensitizes fungi to the antimalarial drug chloroquine |
| title | Cell wall perturbation sensitizes fungi to the antimalarial drug chloroquine |
| title_full | Cell wall perturbation sensitizes fungi to the antimalarial drug chloroquine |
| title_fullStr | Cell wall perturbation sensitizes fungi to the antimalarial drug chloroquine |
| title_full_unstemmed | Cell wall perturbation sensitizes fungi to the antimalarial drug chloroquine |
| title_short | Cell wall perturbation sensitizes fungi to the antimalarial drug chloroquine |
| title_sort | cell wall perturbation sensitizes fungi to the antimalarial drug chloroquine |
| url | https://eprints.nottingham.ac.uk/2343/ https://eprints.nottingham.ac.uk/2343/ https://eprints.nottingham.ac.uk/2343/ |