Miltefosine Reduces the Cytolytic Activity and Virulence of <i>Acinetobacter baumannii</i>

Abstract

Stagnation in antimicrobial development has led to a serious threat to public health because some <i>Acinetobacter baumannii</i> infections have become untreatable. New therapeutics with alternative mechanisms of action to combat <i>A. baumannii</i> are therefore necessary to treat these infections. To this end, the virulence of <i>A. baumannii</i> isolates with various antimicrobial susceptibilities was assessed when the isolates were treated with miltefosine, a phospholipase C inhibitor. Phospholipase C activity is a contributor to <i>A. baumannii</i> virulence associated with hemolysis, cytolysis of A549 human alveolar epithelial cells, and increased mortality in the <i>Galleria mellonella</i> experimental infection model. While the effects on bacterial growth were variable among strains, miltefosine treatment significantly reduced both the hemolytic and cytolytic activity of all treated <i>A. baumannii</i> strains. Additionally, scanning electron microscopy of polarized A549 cells infected with bacteria of the <i>A. baumannii</i> ATCC 19606^T strain 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 of <i>G. mellonella</i> infections, wherein miltefosine treatment of animals infected with ATCC 19606^T significantly decreased mortality. These data demonstrate that inhibition of phospholipase C activity results in the overall reduction of <i>A. baumannii</i> virulence in both <i>in vitro</i> and <i>in vivo</i> models, making miltefosine a viable option for the treatment of <i>A. baumannii</i> infections, particularly those caused by multidrug-resistant isolates.