Attenuation of Acinetobacter baumannii virulence by inhibition of polyphosphate kinase 1 with repurposed drugs

Abstract

Acinetobacter baumannii is clinically one of the most significant pathogens, especially in intensive care settings, because of its multidrug-resistance (MDR). Repurposing of high-affinity drugs is a faster and more plausible approach for combating the emergence of MDR and to tackle bacterial infections. This study was aimed to evaluate the approved drugs potentially inhibiting A. baumannii PPK1 (AbPPK1) mediated synthesis of polyphosphates (polyP). Based on virtual screening, molecular dynamic simulation, and CD spectroscopy for thermal stability, two stable ligands, etoposide and genistein, were found with promising contours for further investigation. Following in vitro inhibition of AbPPK1, the efficacy of selected drugs was further tested against virulence traits of A. baumannii. These drugs significantly reduced the biofilm formation, surface motility in A. baumannii and led to decreased survival under desiccation. In addition to inhibition of PPK1, both drugs increased the expression of polyP degrading enzyme, exopolyphosphatase (PPX), that might be responsible for the decrease in the total cellular polyP. Since polyP modulates the virulence factors in bacteria, destabilization of the polyP pool by these drugs seems particularly striking for their therapeutic applications against A. baumannii.