Research Article: Molecular and cellular responses of the pathogenic fungus Lomentospora prolificans to the antifungal drug voriconazole

Date Published: March 31, 2017

Publisher: Public Library of Science

Author(s): Aize Pellon, Andoni Ramirez-Garcia, Idoia Buldain, Aitziber Antoran, Aitor Rementeria, Fernando L. Hernando, Olaf Kniemeyer.

http://doi.org/10.1371/journal.pone.0174885

Abstract

The filamentous fungus Lomentospora (Scedosporium) prolificans is an emerging opportunistic pathogen associated with fatal infections in patients with disturbed immune function. Unfortunately, conventional therapies are hardly of any use against this fungus due to its intrinsic resistance. Therefore, we performed an integrated study of the L. prolificans responses to the first option to treat these mycoses, namely voriconazole, with the aim of unveiling mechanisms involved in the resistance to this compound. To do that, we used a wide range of techniques, including fluorescence and electron microscopy to study morphological alterations, ion chromatography to measure changes in cell-wall carbohydrate composition, and proteomics-based techniques to identify the proteins differentially expressed under the presence of the drug. Significantly, we showed drastic changes occurring in cell shape after voriconazole exposure, L. prolificans hyphae being shorter and wider than under control conditions. Interestingly, we proved that the architecture and carbohydrate composition of the cell wall had been modified in the presence of the drug. Specifically, L. prolificans constructed a more complex organelle with a higher presence of glucans and mannans. In addition to this, we identified several differentially expressed proteins, including Srp1 and heat shock protein 70 (Hsp70), as the most overexpressed under voriconazole-induced stress conditions. The mechanisms described in this study, which may be directly related to L. prolificans antifungal resistance or tolerance, could be used as targets to improve existing therapies or to develop new ones in order to successfully eliminate these mycoses.

Partial Text

The filamentous fungus Lomentospora prolificans, formerly known as Scedosporium prolificans [1], is an opportunistic pathogen producing mycoses with a wide range of clinical manifestations, from superficial to deep infections. Importantly, when patients suffer from deep immunosuppression, L. prolificans tends to disseminate through the bloodstream due to its capacity to give rise to conidia inside body fluids and tissues, this infection pattern being the most dangerous and fatal [2].

The most challenging characteristic presented by L. prolificans is its inherent resistance to all currently available systemically active antifungal drugs [8], infections caused by this fungus being very difficult to manage and to eliminate. Of all the available antifungal drugs, the most effective agent against L. prolificans cells is VRC which, in combination with terbinafine, brings better results [10], suggesting that disturbing fungal cells in several ways may enhance antifungal drug activities [21]. However, up to now clinical results are not satisfactory and consequently there is an urgent need for novel therapeutic approaches that help to eliminate the fungus. Therefore, since the molecular basis of this species multidrug resistance is completely unknown, the aim of this work was to analyze the changes on L. prolificans cells when exposed to the antifungal drug VRC.

 

Source:

http://doi.org/10.1371/journal.pone.0174885

 

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