title: Tomatidine inhibits replication of Staphylococcus aureus small-colony variants in cystic fibrosis airway epithelial cells.
abstract: Small-colony variants (SCVs) often are associated with chronic Staphylococcus aureus infections, such as those encountered by cystic fibrosis (CF) patients. We report here that tomatidine, the aglycon form of the plant secondary metabolite tomatine, has a potent growth inhibitory activity against SCVs (MIC of 0.12 μg/ml), whereas the growth of normal S. aureus strains was not significantly altered by tomatidine (MIC, >16 μg/ml). The specific action of tomatidine was bacteriostatic for SCVs and was clearly associated with their dysfunctional electron transport system, as the presence of the electron transport inhibitor 4-hydroxy-2-heptylquinoline-N-oxide (HQNO) caused normal S. aureus strains to become susceptible to tomatidine. Inversely, the complementation of SCVs' respiratory deficiency conferred resistance to tomatidine. Tomatidine provoked a general reduction of macromolecular biosynthesis but more specifically affected the incorporation of radiolabeled leucine in proteins of HQNO-treated S. aureus at a concentration corresponding to the MIC against SCVs. Furthermore, tomatidine inhibited the intracellular replication of a clinical SCV in polarized CF-like epithelial cells. Our results suggest that tomatidine eventually will find some use in combination therapy with other traditional antibiotics to eliminate persistent forms of S. aureus.
authors.affiliation: CEVDM, Université de Sherbrooke, Département de Biologie, Faculté des Sciences, 2500 Boul. Université, Sherbrooke, Quebec, Canada, J1K2R1.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Mitchell
authors.forename: Mariza
authors.initials: M
authors.lastname: Gattuso
authors.forename: Gilles
authors.initials: G
authors.lastname: Grondin
authors.forename: Éric
authors.initials: É
authors.lastname: Marsault
authors.forename: Kamal
authors.initials: K
authors.lastname: Bouarab
authors.forename: François
authors.initials: F
authors.lastname: Malouin
mesh_terms: D002460:Cell Line; D003550:Cystic Fibrosis / Q000150:complications* / Q000382:microbiology*; D005839:Gentamicins / Q000494:pharmacology; D006801:Humans; D006912:Hydroxyquinolines / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D013203:Staphylococcal Infections / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects*; D014053:Tomatine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D005839:Gentamicins; D006912:Hydroxyquinolines; C001333:2-(n-heptyl)-4-hydroxyquinoline N-oxide; C003677:tomatidine; D014053:Tomatine