Pacing across the membrane: the novel PACE family of efflux pumps is widespread in Gram-negative pathogens

Karl A Hassan,Qi Liu,Liam D.H Elbourne,Irshad Ahmad,David Sharples,Varsha Naidu,Chak Lam Chan,Liping Li,Steven P.D Harborne,Alaska Pokhrel,Vincent L.G Postis,Adrian Goldman,Peter J.F Henderson,Ian T Paulsen

doi:10.1016/j.resmic.2018.01.001

Abstract

The proteobacterial antimicrobial compound efflux (PACE) family of transport proteins was only recently described. PACE family transport proteins can confer resistance to a range of biocides used as disinfectants and antiseptics, and are encoded by many important Gram-negative human pathogens. However, we are only just beginning to appreciate the range of functions and the mechanism(s) of transport operating in these proteins. Genes encoding PACE family proteins are typically conserved in the core genomes of bacterial species rather than on recently acquired mobile genetic elements, suggesting that they confer important core functions in addition to biocide resistance. Three-dimensional structural information is not yet available for PACE family proteins. However, PACE proteins have several very highly conserved amino acid sequence motifs that are likely to be important for substrate transport. PACE proteins also display strong amino acid sequence conservation between their N and C-terminal halves, suggesting that they evolved by duplication of an ancestral protein comprised of two transmembrane helices. In light of their drug resistance functions in Gram-negative pathogens, PACE proteins should be the subject of detailed future investigation.

Highlights

In the broadest sense, drug resistance may arise in actively growing bacterial cells in two distinct ways: either the drug target site is protected from the toxic activities of the drug by modification or bypass, or the drug cannot reach the target site due to degradation, sequestration, reduced cellular entry or active efflux
Similar to A. baumannii, P. aeruginosa isolates have two proteobacterial antimicrobial compound efflux (PACE) proteins encoded in the core genome and one in the accessory genome, which is found in only a few strains, and B. cenocepacia strains encode three PACE pumps in their core genome [7]
PACE family proteins display somewhat restricted drug substrate recognition profiles, which include primarily synthetic biocides such as chlorhexidine and acriflavine, rather than the multitudes of diverse antibiotics and biocides recognised by transport proteins from families such as the resistance-nodulationcell division (RND) superfamily

Summary

Introduction

Drug resistance may arise in actively growing bacterial cells in two distinct ways: either the drug target site is protected from the toxic activities of the drug by modification or bypass, or the drug cannot reach the target site due to degradation, sequestration, reduced cellular entry or active efflux. The demonstration that many AceI homologues are able to confer resistance to compounds such as proflavine and acriflavine presented the possibility of assaying transport by measuring their fluorescence in real time [12]. The observation that several AceI homologues can confer resistance to multiple biocides and can mediate transport of the fluorescent substrates proflavine and acriflavine led to their designation as a new family of efflux pumps. This family was called the Proteobacterial Antimicrobial Compound Efflux (PACE) family, due to their abundance in Proteobacteria [3]. PACE proteins are a family of multidrug efflux systems conserved across many Gram-negative pathogens

Predicted topology and sequence conservation in PACE pumps

Conservation of PACE family genes

Evolution of the PACE family

Findings

Concluding remarks