title: Bactericidal Effect of Tomatidine-Tobramycin Combination against Methicillin-Resistant Staphylococcus aureus and Pseudomonas aeruginosa Is Enhanced by Interspecific Small-Molecule Interactions.
abstract: This study investigated the antibacterial activity of the plant alkaloid tomatidine (TO) against Staphylococcus aureus grown in the presence of Pseudomonas aeruginosa. Since the P. aeruginosa exoproduct 4-hydroxy-2-heptylquinoline-N-oxide (HQNO) is known to cause a respiratory deficiency in S. aureus and respiratory-deficient S. aureus are known to be hypersensitive to TO, we assessed kill kinetics of TO (8 μg/ml) against S. aureus in coculture with P. aeruginosa. Kill kinetics were also assessed using P. aeruginosa mutants deficient in the production of different exoproducts and quorum sensing-related compounds. After 24 h in coculture, TO increased the killing of S. aureus by 3.4 log10 CFU/ml in comparison to that observed in a coculture without TO. The effect of TO was abolished when S. aureus was in coculture with the lasR rhlR, pqsA, pqsL, or lasA mutant of P. aeruginosa. The bactericidal effect of TO against S. aureus in coculture with the pqsL mutant was restored by supplemental HQNO. In an S. aureus monoculture, the combination of HQNO and TO was bacteriostatic, indicating that the pqsL mutant produced an additional factor required for the bactericidal effect. The bactericidal activity of TO was also observed against a tobramycin-resistant methicillin-resistant S. aureus (MRSA) in coculture with P. aeruginosa, and the addition of tobramycin significantly suppressed the growth of both microorganisms. TO shows a strong bactericidal effect against S. aureus when cocultured with P. aeruginosa. The combination of TO and tobramycin may represent a new treatment approach for cystic fibrosis patients frequently cocolonized by MRSA and P. aeruginosa.
authors.affiliation: Centre d'Étude et de Valorisation de la Diversité Microbienne (CEVDM), Département de biologie, Faculté des sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Boulanger
authors.affiliation: Centre d'Étude et de Valorisation de la Diversité Microbienne (CEVDM), Département de biologie, Faculté des sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Mitchell
authors.affiliation: Centre d'Étude et de Valorisation de la Diversité Microbienne (CEVDM), Département de biologie, Faculté des sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Kamal
authors.initials: K
authors.lastname: Bouarab
authors.affiliation: Département de pharmacologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Éric
authors.initials: É
authors.lastname: Marsault
authors.affiliation: Département de médecine, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: André
authors.initials: A
authors.lastname: Cantin
authors.affiliation: Département de microbiologie et infectiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Eric H
authors.initials: EH
authors.lastname: Frost
authors.affiliation: INRS-Institut Armand-Frappier, Laval, Quebec, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Déziel
authors.affiliation: Centre d'Étude et de Valorisation de la Diversité Microbienne (CEVDM), Département de biologie, Faculté des sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada francois.malouin@usherbrooke.ca.
authors.forename: François
authors.initials: F
authors.lastname: Malouin
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D018920:Coculture Techniques; D004357:Drug Synergism; D006912:Hydroxyquinolines / Q000378:metabolism; D045726:Metalloproteases / Q000235:genetics; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D009154:Mutation; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics; D053038:Quorum Sensing; D014031:Tobramycin / Q000494:pharmacology*; D014053:Tomatine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D006912:Hydroxyquinolines; C080365:LasR protein, Pseudomonas aeruginosa; D015534:Trans-Activators; D037521:Virulence Factors; C001333:2-(n-heptyl)-4-hydroxyquinoline N-oxide; C003677:tomatidine; D014053:Tomatine; C548166:LasA protein, Pseudomonas aeruginosa; D045726:Metalloproteases; D014031:Tobramycin