Bactericidal Effect of Tomatidine-Tobramycin Combination against Methicillin-Resistant Staphylococcus aureus and Pseudomonas aeruginosa Is Enhanced by Interspecific Small-Molecule Interactions

• Published in: Antimicrobial agents and chemotherapy 2015-12, Vol.59 (12), p.7458-7464
• Main Authors: Boulanger, Simon, Mitchell, Gabriel, Bouarab, Kamal, Marsault, Éric, Cantin, André, Frost, Eric H, Déziel, Eric, Malouin, François
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents; Anti-Bacterial Agents - pharmacology; Bacterial Proteins - genetics; Bacteriology; Coculture Techniques; Drug Synergism; Hydroxyquinolines - metabolism; Life Sciences; Mechanisms of Action: Physiological Effects; Metalloproteases - genetics; Methicillin-Resistant Staphylococcus aureus; Methicillin-Resistant Staphylococcus aureus - drug effects; Microbial Sensitivity Tests; Microbiology and Parasitology; Mutation; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - genetics; Quorum Sensing; Staphylococcus aureus; Tobramycin; Tobramycin - pharmacology; Tomatine; Tomatine - analogs & derivatives; Tomatine - pharmacology; Trans-Activators - genetics; Virulence Factors - genetics
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.01711-15

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.