title: Tomatidine acts in synergy with aminoglycoside antibiotics against multiresistant Staphylococcus aureus and prevents virulence gene expression.
abstract: OBJECTIVE
  This study characterized the multiple biological activities of the natural compound tomatidine against Staphylococcus aureus. Notably, this work examined the antibacterial activity of tomatidine in combination with other antibiotics and the influence of this compound on the expression of virulence factors in S. aureus.
  
  
  METHODS
  The effect of tomatidine on the susceptibility of S. aureus to several antibiotic classes was determined by a broth microdilution procedure and a chequerboard protocol to measure fractional inhibitory concentration indices and to reveal drug interactions. Time-kill experiments for aminoglycoside/tomatidine combinations were also performed. The haemolytic ability of several strains in the presence of tomatidine was measured on blood agar plates and the expression of virulence-associated genes in strain ATCC 29213 treated with tomatidine was monitored by quantitative PCR.
  
  
  RESULTS
  Tomatidine specifically potentiated the inhibitory effect of aminoglycosides but not of other classes of drugs. This potentiating effect was observed against strains of different clinical origins (human blood, cystic fibrosis airways, osteomyelitis, skin tissues and bovine mastitis), including aminoglycoside-resistant bacteria possessing the aac(6')-aph(2″), ant(4')-Ia and aph(3')-IIIa genes. The killing kinetics for the combination of aminoglycosides with tomatidine revealed strong bactericidal activity. Although tomatidine did not possess growth-inhibitory activity of its own against prototypical S. aureus, it inhibited the haemolytic activity of several strains and, more specifically, blocked the expression of several genes normally influenced by the agr system.
  
  
  CONCLUSIONS
  These results show that tomatidine is an aminoglycoside potentiator that also acts as an anti-virulence agent targeting both antibiotic-susceptible and antibiotic-resistant S. aureus.
authors: Centre d'Étude et de Valorisation de la Diversité Microbienne (CEVDM), Département de biologie, Faculté des sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors: Gabriel
authors: G
authors: Mitchell
authors: Myriame
authors: M
authors: Lafrance
authors: Simon
authors: S
authors: Boulanger
authors: David Lalonde
authors: DL
authors: Séguin
authors: Isabelle
authors: I
authors: Guay
authors: Mariza
authors: M
authors: Gattuso
authors: Eric
authors: E
authors: Marsault
authors: Kamal
authors: K
authors: Bouarab
authors: François
authors: F
authors: Malouin
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003470:Culture Media / Q000737:chemistry; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D004357:Drug Synergism; D004912:Erythrocytes / Q000382:microbiology; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D006460:Hemolysin Proteins / Q000037:antagonists & inhibitors; D006461:Hemolysis; D006736:Horses; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000472:pathogenicity; D013997:Time Factors; D014053:Tomatine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014774:Virulence; D037521:Virulence Factors / Q000037:antagonists & inhibitors*
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D003470:Culture Media; D006460:Hemolysin Proteins; D037521:Virulence Factors; C003677:tomatidine; D014053:Tomatine