Impact of Iron Chelators on Growth and Expression of Iron-Related Genes of Cryptococcus species

Ref ID: 18768

Author:

M. Chayakulkeeree, MD, PhD – Assistant Professor, T. Tangkoskul, PhD – Research Asistant, S. Tiengrim, MS – Research Associate, S. Onsomearng, BSc – Research Assistant;

Author address:

Siriraj Hosp., Mahidol Univ., Bangkok, Thailand.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: The iron chelator, deferasirox (DFX), has shown to have fungicidal activity against Rhizopus. This work is to investigate the potential antifungal activity of iron chelators, deferoxamine (DFO) and DFX, against cryptococcal isolates and their impacts on expression of cryptococcal iron-related genes. Methods: C. neoformans and C. gattii were used to determine the minimal inhibitory concentration (MIC) of DFO and DFX and the fractional inhibitory concentration (FIC) of the combinations between the iron chelators and amphotericin B (AMB). Growth curves of cryptococcal strains in exposure to iron chelators, with and without AMB, were performed. Expression of cryptococcal CFT1, CFT2, and CIR1 genes was determined using semi-quantitative real-time PCR. Results: Both DFO and DFX alone show no antifungal activity against Cryptococcus strains. However, when combined with AMB, the MIC of both DFO and DFX decreased from >200 µg/ml to 6.25 µg/ml for serotypes A and AD. For serotypes B, C and D, the MIC of DFO and DFX decreased from > 200 µg/ml to 6.25 and 12.5 µg/ml, respectively. Likewise, the MIC of AMB decreased for one dilution in all strains when combined with iron chelators, giving the FIC of 0.5 and 1 for DFO+AMB and DFX+AMB, respectively. Growth curve of C. neoformans (serotype A and D) showed a significant growth retardation of the yeast cells when incubated with a combination of sub-MIC concentration of AMB and DFO, compared with either AMB or DFO alone. However, C. gattii (serotype B and C) exhibited significantly less extent in growth retardation in media with DFO+AMB. In contrast, cryptococcal growth retardation was not observed, or minimal, when DFX is used in combination with AMB in all serotypes. When C. neoformans was grown in DFO, the CFT1, CFT2 and CIR1 were up-regulated for 3.3, 2.6, and 1.8 times, respectively. With DFX, the CFT1, CFT2 and CIR1 were up-regulated for 4.1, 2.2, and 10.1 times, respectively. Conclusions: The extent of synergistic effect between DFO+AMB was more than that of DFX+AMB and this is different to Zygomycetes in which DFO enhances fungal growth. CIR1 expression seems to be the major mechanism to compensate growth inhibitory effect of DFX but not DFO.

Abstract Number: M-976

Conference Poster: y

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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