Exploring the physiological substrates of the prototypical pace family efflux pump Ace1

Hassan KA1,2,3, Naidu V2, Liu Q2, Edgerton J3, Fahmy L3, Li L2, Mettrick KA1, Jackson SM3, Ahmad I3, Sharples D3, Henderson PJF3 and Paulsen IT2

  1. School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW, Australia.
  2. Department of Molecular Sciences, Macquarie University, North Ryde, NSW, Australia.
  3. School of BioMedical Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK.

Resistance to antimicrobials is one of the most pressing health issues of our time. Multidrug efflux pumps have gained notoriety as a major and highly promiscuous class of drug resistance determinants that contribute to the failure of antibiotic therapy and promote the persistence of pathogens in hospitals. Despite their widely-studied roles in drug resistance, for many multidrug efflux pumps drug transport is likely to be a fortuitous side reaction made possible by flexible substrate binding sites that have become beneficial to host organisms living under highly drug selective conditions in hospitals. The core functions of these pumps are likely to be linked to the physiology of the organism and the environments in which they evolved. This is almost certainly true for the AceI transport protein, the prototype for the novel PACE family of efflux pumps. The gene encoding AceI is conserved across all Acinetobacter baumannii strains to have had their genomes sequenced, indicating an ancient origin and long term pressure for gene maintenance. Paradoxically, its only characterised substrate is chlorhexidine, which, although widely used as an antiseptic today, is purely synthetic and has been produced only since last century. In this talk I will describe our progress in deciphering the core physiological functions of the AceI protein, as well as its mode of energisation.