title: In vitro activity of aminosterols against yeasts involved in blood stream infections.
abstract: Squalamine and other aminosterols have demonstrated interesting antimicrobial activities against clinical bacterial isolates and a limited number of reference yeast strains. We aimed to test whether squalamine and a synthetic aminosterol derivative (ASD) display any in vitro activity comparable to currently available systemic antifungals, an acceptable safety index, as well as to provide insights into their mechanism of action. The minimum inhibitory concentrations (MICs) of squalamine, ASD and available antifungals were determined against 21 yeast isolates that were recovered from cases of fungemia. Remarkably, homogeneous MICs ranging from 8-16 mg/L and from 1-2 mg/L were noted for squalamine and ASD, respectively, as opposes the heterogeneous in vitro activity of available systemic antifungals. Aminosterols induced haemolysis, a surrogate for toxic effects to mammalian cells, at concentrations high above their MICs. In time-kill studies, killing was as fast with ASD as with amphotericin B. Both aminosterols induced a time-dependent disruption of yeast membrane, as evidenced by gradual increase of ATP efflux. In conclusion, our preliminary data indicate that aminosterols have the potential to be further developed as antifungals. Additional work is warranted to assess their toxicity and activity in experimental models.
authors.affiliation: URMITE UMR 6236, CNRS-IRD, Faculté de Médecine et de Pharmacie, Marseille, France.
authors.forename: Kamel
authors.initials: K
authors.lastname: Alhanout
authors.forename: Lamia
authors.initials: L
authors.lastname: Djouhri
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vidal
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Brunel
authors.forename: Renaud
authors.initials: R
authors.lastname: Piarroux
authors.forename: Stéphane
authors.initials: S
authors.lastname: Ranque
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000935:Antifungal Agents / Q000494:pharmacology*; D002777:Cholestanols / Q000494:pharmacology*; D016469:Fungemia / Q000382:microbiology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D013997:Time Factors; D015003:Yeasts / Q000187:drug effects* / Q000302:isolation & purification*
chemical_list: D000935:Antifungal Agents; D002777:Cholestanols; D000255:Adenosine Triphosphate; C079655:squalamine