Invasive
infections due to Staphylococcus aureus, including methicillin-resistant S. aureus are prevalent and life-threatening. Combinations of
antibiotic therapy have been employed in many clinical settings for improving therapeutic efficacy, reducing
side effects of drugs, and development of antibiotic resistance.
Pleuromutilins have a potential to be developed as a new class of
antibiotics for systemic use in humans. In the current study, we investigated the relationship between
pleuromutilins, including
valnemulin,
tiamulin, and
retapamulin, and 13 other
antibiotics representing different mechanisms of action, against
methicillin-susceptible and -resistant S. aureus both in vitro and in an experimental Galleria mellonella model. In vitro synergistic effects were observed in combination of all three study
pleuromutilins with
tetracycline (TET) by standard checkerboard and/or time-kill assays. In addition, the combination of
pleuromutilins with
ciprofloxacin or
enrofloxacin showed antagonistic effects, while the rest combinations presented indifferent effects. Importantly, all study
pleuromutilins in combination with TET significantly enhanced survival rates as compared to the single drug treatment in the G. mellonella model caused by S. aureus strains. Taken together, these results demonstrated synergy effects between
pleuromutilins and TET against S. aureus both in vitro and in vivo.