Miltefosine Reduces the Cytolytic Activity and Virulence ofAcinetobacter baumannii
ABSTRACTStagnation in antimicrobial development has led to a serious threat to public health because someAcinetobacter baumanniiinfections have become untreatable. New therapeutics with alternative mechanisms of action to combatA. baumanniiare therefore necessary to treat these infections. To this end, the virulence ofA. baumanniiisolates with various antimicrobial susceptibilities was assessed when the isolates were treated with miltefosine, a phospholipase C inhibitor. Phospholipase C activity is a contributor toA. baumanniivirulence associated with hemolysis, cytolysis of A549 human alveolar epithelial cells, and increased mortality in theGalleria mellonellaexperimental infection model. While the effects on bacterial growth were variable among strains, miltefosine treatment significantly reduced both the hemolytic and cytolytic activity of all treatedA. baumanniistrains. Additionally, scanning electron microscopy of polarized A549 cells infected with bacteria of theA. baumanniiATCC 19606Tstrain or the AB5075 multidrug-resistant isolate showed a decrease in A549 cell damage with a concomitant increase in the presence of A549 surfactant upon administration of miltefosine. The therapeutic ability of miltefosine was further supported by the results ofG. mellonellainfections, wherein miltefosine treatment of animals infected with ATCC 19606Tsignificantly decreased mortality. These data demonstrate that inhibition of phospholipase C activity results in the overall reduction ofA. baumanniivirulence in bothin vitroandin vivomodels, making miltefosine a viable option for the treatment ofA. baumanniiinfections, particularly those caused by multidrug-resistant isolates.