Cell-wall Perturbation Sensitizes Fungi to the Antimalarial Drug Chloroquine.
Antimicrob Agents Chemother. 2013 Jun 3;
Authors: Islahudin F, Khozoie C, Bates S, Ting KN, Pleass RJ, Avery SV
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 CQ action in fungi, including the yeast model Saccharomyces cerevisiae. The genome-wide 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 was accumulated to higher levels in cells with perturbed cell walls; CQ uptake was two- to three-fold greater in bck1Δ or slt2Δ mutants than in wild type yeast. CQ toxicity was synergistic with that of the major cell wall-targeting antifungal drug, caspofungin. The MIC for caspofungin against the yeast pathogen Candida albicans was decreased two-fold by 250 μM CQ, and by up to five-fold at higher CQ concentrations. Similar effects were seen in C. 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.
PMID: 23733464 [PubMed - as supplied by publisher]