Synergistic Effect of Pleuromutilins with Other Antimicrobial Agents against Staphylococcus aureus In Vitro and in an Experimental Galleria mellonella Model

Abstract

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.

Galleria mellonella as a consolidated in vivo model hosts: New developments in antibacterial strategies and novel drug testing

“…Among all combinations, tetracycline and valnemulin was the best combination. The combinations with ciprofloxacin did not improve the larvae survival rates as compared with monotherapy [75].…”

Essential Oil, Extracts, and Sesquiterpenes Obtained From the Heartwood of Pilgerodendron uviferum Act as Potential Inhibitors of the Staphylococcus aureus NorA Multidrug Efflux Pump

“…The results obtained in synergism assays, are coincident with those previous in vitro studies which showed a synergistic effect between plant extracts and/or isolated compounds with different classes of antibiotics against sensitive and multidrug resistant pathogenic strains. It has also been determined that these combinations reduced the minimum inhibitory concentration of antibiotics in different S. aureus strains (Chung et al, 2011; Langeveld et al, 2014; Bag and Chattopadhyay, 2015; Dong et al, 2017). In addition, Magi et al (2015), described that carvacrol, the major component of the EOs of Origanum and Thymus plants act in synergism with erythromycin against 21 of 32 clinical erythromycin-resistant Streptococci, with reduction of the erythromycin MIC up to 2,048-fold.…”

Galleria mellonella experimental model for bat fungal pathogen Pseudogymnoascus destructans and human fungal pathogen Pseudogymnoascus pannorum

“…Galleria mellonella models have become invaluable to study cellular and humoral immune responses against pathogens [31–33], epigenetic influences on the evolution of virulence [32,34,35], and for development and testing antimicrobials [36–39]. It is relevant to add that the complete genomes of P. destructans and G. mellonella have become available recently [40,41].…”