Poster Presentation BACPATH 2017

Cellular and regulatory mechanisms involved in pentamidine resistance in Acinetobacter baumannii (#101)

Felise G Adams 1 , Uwe H Stroeher 1 , Karl A Hassan 2 , Melissa H Brown 1
  1. School of Biological Sciences , Flinders University of South Australia, Adelaide, SA, Australia
  2. Department of Chemistry and Biomolecular Sciences , Macquarie University, Sydney, New South Wales, Australia

Acinetobacter baumannii is a problematic bacterial pathogen that causes life-threatening disease states in humans. Infections caused by A. baumannii have become increasingly difficult to treat due to its ability to acquire or upregulate antimicrobial resistance determinants. Although a number of virulence factors for this pathogen are known, the regulation mechanisms controlling these genes are ill-defined. Eleven classical two component signal transduction systems (TCSTS) have been identified in A. baumannii strain ATCC 17978. Of these, the TCSTS adeRS controls expression of the adeABC multidrug efflux pump in many A. baumannii isolates. To assess the function of this TCSTS in A. baumannii ATCC 17978, a ∆adeRS derivative was generated. Assessment of this deletion by RNA-sequencing revealed the modulation of transcriptional levels of more than 300 genes by ≥2-fold. Inactivation of adeRS resulted in decreased resistance towards a set of dicationic compounds, with an 8-fold decrease to pentamidine observed. Deletion of adeAB mirrored ∆adeRS resistance levels thereby identifying these dicationic compounds as AdeAB substrates. To identify alternative mechanisms of pentamidine resistance growth of ∆adeRS under a range of conditions was assessed. Biolog phenotypic arrays identified a number of carbon sources that influenced pentamidine resistance. Furthermore, chelation of iron by addition of 2,2’-dipyridyl or organic acids potentiated pentamidine susceptibility. This study is the first to identify that AdeAB confers intrinsic resistance to a set of dicationic antimicrobial compounds, a process regulated by AdeRS. Furthermore, resistance to pentamidine can be significantly altered depending on growth conditions, highlighting new molecular interactions which could potentially affect the efficacy of this antimicrobial as a prospective adjuvant to treat troublesome A. baumannii infections.