title: Synergy and antagonism between iron chelators and antifungal drugs in Cryptococcus.
abstract: Fungal infections remain very difficult to treat, and developing new antifungal drugs is difficult and expensive. Recent approaches therefore seek to augment existing antifungals with synergistic agents that can lower the therapeutic dose, increase efficacy and prevent resistance from developing. Iron limitation can inhibit microbial growth, and iron chelators have been employed to treat fungal infections. In this study, chequerboard testing was used to explore combinations of iron chelators with antifungal agents against pathogenic Cryptococcus spp. with the aim of determining how disruption to iron homeostasis affects antifungal susceptibility. The iron chelators ethylenediaminetetraacetic acid (EDTA), deferoxamine (DFO), deferiprone (DFP), deferasirox (DSX), ciclopirox olamine and lactoferrin (LF) were paired with the antifungal agents amphotericin B (AmB), fluconazole, itraconazole, voriconazole and caspofungin. All chelators except for DFO increased the efficacy of AmB, and significant synergy was seen between AmB and LF for all Cryptococcus strains. Addition of exogenous iron rescued cells from the antifungal effect of LF alone but could not prevent inhibition by AmB + LF, indicating that synergy was not due primarily to iron chelation but to other properties of LF that were potentiated in the presence of AmB. Significant synergy was not seen consistently for other antifungal-chelator combinations, and EDTA, DSX and DFP antagonised the activity of azole drugs in strains of Cryptococcus neoformans var. grubii. This study highlights the range of interactions that can be induced by chelators and indicates that most antifungal drugs are not enhanced by iron limitation in Cryptococcus.
authors.affiliation: School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, Australia.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Lai
authors.affiliation: School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, Australia.
authors.forename: Leona T
authors.initials: LT
authors.lastname: Campbell
authors.affiliation: Systems Biology Initiative, School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW, Australia.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Wilkins
authors.affiliation: Systems Biology Initiative, School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW, Australia.
authors.forename: Chi Nam Ignatius
authors.initials: CN
authors.lastname: Pang
authors.affiliation: Centre for Infectious Diseases and Microbiology Laboratory Services, ICPMR, Westmead Hospital and the University of Sydney, Sydney, NSW, Australia.
authors.forename: Sharon
authors.initials: S
authors.lastname: Chen
authors.affiliation: School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, Australia. Electronic address: dee.carter@sydney.edu.au.
authors.forename: Dee A
authors.initials: DA
authors.lastname: Carter
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D003454:Cryptococcus / Q000187:drug effects*; D004347:Drug Interactions; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests
chemical_list: D000935:Antifungal Agents; D007502:Iron Chelating Agents
keywords: Amphotericin B; Antifungal drug synergy; Cryptococcus; Lactoferrin; Metal ion homeostasis