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Abstract
Background: Members of the genus Scedosporium are emerging human pathogens, causing a wide range of infections. Their treatment means a challenge for clinicians, mostly because of the low susceptibility of these causative agents to conventional antifungal drugs. New alternative therapeutic approaches are required for better clinical outcomes. Cysteine and its derivatives alone or in combinations with antifungal drugs might have improved antifungal effects against Scedosporium species. Methods: The in vitro antifungal effects of two cysteine forms and three of their derivatives (i.e., D-cysteine, L-cysteine, L-cysteine-methyl ester hydrochloride, N-isobutyryl-D-cysteine, and N-isobutyryl-L-cysteine) were determined using the CLSI M38-A2 broth microdilution method. The in vitro drug interactions between the most effective cysteine derivatives and some conventional antifungal drugs were also investigated using checkerboard assays in case of four clinical isolates. Results: L-cysteine-methyl ester hydrochloride proved to be the most effective among the investigated compounds. N-isobutyryl-L-cysteine exhibited antifungal activity against one Scedosporium aurantiacum strain only. D-cysteine, L-cysteine and N-isobutyryl-D-cysteine proved to be ineffective against Scedosporium spp. in the investigated concentration range. No significant differences were found in the susceptibilities between environmental and clinical isolates. L-cysteine-methyl ester hydrochloride could interact synergistically with amphotericin B, caspofungin, terbinafine and voriconazole. Antagonistic interactions were not observed between the investigated compounds. Conclusions: The present study provides an evidence for the in vitro antifungal activity of L-cysteinemethyl ester hydrochloride and the synergistic interactions between this cysteine derivative and conventional antifungal agents. Based on our results, L-cysteine-methyl ester hydrochloride in combination with antifungal drugs could be applicable in the treatment of human Scedosporium infections in the future. However, further studies are required to clarify the antifungal mechanism of L-cysteine-methyl ester hydrochloride and to investigate its activity in vivo.
Highlights
Scedosporium species are emerging human pathogens, responsible for a broad spectrum of infections, including superficial or deep localized diseases in immunocompetent hosts, and disseminated infections in immunocompromised or in near-drowning patients [1]
The present study provides an evidence for the in vitro antifungal activity of L-cysteinemethyl ester hydrochloride and the synergistic interactions between this cysteine derivative and conventional antifungal agents
L-cysteine-methyl ester hydrochloride in combination with antifungal drugs could be applicable in the treatment of human Scedosporium infections in the future
Summary
Scedosporium species are emerging human pathogens, responsible for a broad spectrum of infections, including superficial or deep localized diseases in immunocompetent hosts, and disseminated infections in immunocompromised or in near-drowning patients [1]. According to a recent clinical study in Spain, the members of this genus are the second most frequently isolated filamentous fungi from human infections after Aspergillus species [3]. The accurate identification of the causative agent is crucial to find the most effective therapeutic approach, since the antifungal susceptibility profile of Scedosporium species is different from those of hyaline filamentous fungi, and varies within the genus itself [2]. Another challenge in the treatment is the frequently observed antifungal resistance of the Scedosporium isolates to conventional antifungal agents [1]. New therapeutic strategies are required beside of the currently available ones
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