pH Signaling Inhibition in Candida albicans Leads to Enhanced Activity and Restore Fungicidal Effect of Ergosterol Synthesis Inhibitors

Ref ID: 18769

Author:

S. Sahli, MS – MS 1, S. Boulahfa, MS – MS 1, M. Cornet, MD (Doctor of Medicine) – Professor1,2;

Author address:

1Université Joseph Fourier, Grenoble, France, 2CHU, Grenoble, France.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: The role of the pH regulation in antifungal activity was suggested when the azole compound D0870 showed enhanced fungicidal effect against C. neoformans at low pH. Later, azoles susceptibility tests in Candida sp. showed an inhibition of the trailing effect under acidic conditions. pH regulation in yeasts is mainly controlled by the Rim pathway: a cascade of seven proteins triggered at neutral-alkaline pH and inactivated in acidic conditions. Methods: We analyzed the susceptibility of six C. albicans rim deleted strains and a control strain (DAY286) to the triazoles, other ergosterol synthesis inhibitors (terbinafine, fenpropimorph) and amphotericin B. MICs were determined using the M27-A3 CLSI microdilution method. Results are means calculated from at least 10 independent experiments. Cidality assays were performed using the cells from the MIC assays that were spotted onto rich and solid medium without any antifungal compounds. Results: All the rim mutants showed significant reduction of the MICs to all the ergosterol synthesis inhibitors other than terbinafine (Table 1). On spotted assays, the control strain was able to grow after exposure to all concentrations of all the ergosterol synthesis inhibitors. Rim inhibition in all mutants enhanced cidality of all the ergosterol synthesis inhibitors except terbinafine, with the more severe effect for the triazoles. Interestingly, amphotericin B which independently targets the ergosterol of the membrane, most probably through a mechanical interaction, showed conserved activity in the rim deleted strains.
Conclusions: Our results support the hypothesis that targeting the Rim pH signaling pathway may constitute a novel approach to enhance fungal inhibition and killing.

Abstract Number: M-983

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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