Cell wall perturbation sensitizes fungi to the antimalarial drug chloroquine

Farida Hanim Islahudin, Combiz Khozoie, Steven Bates, Kang Nee Ting, Richard J. Pleass, Simon V. Avery

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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 bck1 and slt2 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 bck1 and slt2 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 MCQ 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.

Original languageEnglish
Pages (from-to)3889-3896
Number of pages8
JournalAntimicrobial Agents and Chemotherapy
Volume57
Issue number8
DOIs
Publication statusPublished - Aug 2013
Externally publishedYes

Fingerprint

Chloroquine
Antimalarials
Cell Wall
Fungi
caspofungin
Yeasts
Drug Delivery Systems
Candida glabrata
Phenotype
Sonication
Aspergillus fumigatus
Sorbitol
Cellular Structures
Therapeutics
Caffeine
Candida albicans
Saccharomyces cerevisiae
Hypersensitivity

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Cell wall perturbation sensitizes fungi to the antimalarial drug chloroquine. / Islahudin, Farida Hanim; Khozoie, Combiz; Bates, Steven; Ting, Kang Nee; Pleass, Richard J.; Avery, Simon V.

In: Antimicrobial Agents and Chemotherapy, Vol. 57, No. 8, 08.2013, p. 3889-3896.

Research output: Contribution to journalArticle

Islahudin, Farida Hanim ; Khozoie, Combiz ; Bates, Steven ; Ting, Kang Nee ; Pleass, Richard J. ; Avery, Simon V. / Cell wall perturbation sensitizes fungi to the antimalarial drug chloroquine. In: Antimicrobial Agents and Chemotherapy. 2013 ; Vol. 57, No. 8. pp. 3889-3896.
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