Antibiotic resistance has become a major hurdle for successful treatment of several infections resulting in increased length of stay in hospitals and mortality. One of the notorious pathogens that wreaks havoc due to antibiotic resistance is Staphylococcus aureus. There is an urgent need to discover and understand the function of newer molecules that could serve in the arsenal to combat these bacteria. Our recent work identified important structural determinants of stilbenes that could aid in better antibacterial activity and identified Dimer stilbene (DS) as a potent inhibitor of S. aureus. Contrasting reports exist in literature about the combination of stilbenes with different antibiotics. In this study we evaluated the ability of DS to synergize with different classes of antibiotics. A screen revealed DS exhibited positive co-operativity with antibiotics that target protein synthesis. DS exhibited synergy with the aminoglycoside kanamycin and additive effect with tetracycline. Resistance generation to DS was null while to that of kanamycin was rapid. Kanamycin resistant S. aureus was equally susceptible to DS compared to wildtype. The efficacy of DS against clinical isolates susceptible and resistant to methicillin were similar. Laboratory generated kanamycin resistant strain and clinical strains were sensitized to kanamycin by pre-treatment with DS. DS cured S. aureus infection in mice as a standalone drug as well as in conjunction with kanamycin. Synergy with kanamycin was also observed in other stilbenes apart from DS. Thus our study reveals stilbenes could be exploited towards combating S. aureus infections either as standalone drugs or in combination with existing antibiotics.
Keywords: Aminoglycosides; Antibiotic resistance; Dimer stilbene; Resveratrol analogues; Synergy.
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