MexXY multidrug efflux system of Pseudomonas aeruginosa

Yuji Morita,Junko Tomida,Yoshiaki Kawamura

doi:10.3389/fmicb.2012.00408

Abstract

Anti-pseudomonas aminoglycosides, such as amikacin and tobramycin, are used in the treatment of Pseudomonas aeruginosa infections. However, their use is linked to the development of resistance. During the last decade, the MexXY multidrug efflux system has been comprehensively studied, and numerous reports of laboratory and clinical isolates have been published. This system has been increasingly recognized as one of the primary determinants of aminoglycoside resistance in P. aeruginosa. In P. aeruginosa cystic fibrosis isolates, upregulation of the pump is considered the most common mechanism of aminoglycoside resistance. Non-fermentative Gram-negative pathogens possessing very close MexXY orthologs such as Achromobacter xylosoxidans and various Burkholderia species (e.g., Burkholderia pseudomallei and B. cepacia complexes), but not B. gladioli, are intrinsically resistant to aminoglycosides. Here, we summarize the properties (e.g., discovery, mechanism, gene expression, clinical significance) of the P. aeruginosa MexXY pump and other aminoglycoside efflux pumps such as AcrD of Escherichia coli, AmrAB-OprA of B. pseudomallei, and AdeABC of Acinetobacter baumannii. MexXY inducibility of the PA5471 gene product, which is dependent on ribosome inhibition or oxidative stress, is noteworthy. Moreover, the discovery of the cognate outer membrane component (OprA) of MexXY in the multidrug-resistant clinical isolate PA7, serotype O12 deserves special attention.

Highlights

Pseudomonas aeruginosa has been recognized as an increasingly important and worrisome species in health care-associated infections (Poole, 2011)
The prospects of finding new antibiotics for Gram-negative pathogens are poor because of the low permeability of their outer membrane barriers and the presence of multidrug efflux transporters (Fischbach and Walsh, 2009). To combat these bacteria efficiently, it is necessary to understand the molecular basis of the efflux mechanisms involved in limiting the intracellular concentration of many antibiotics (Nikaido and Pages, 2012)
STRUCTURE AND FUNCTION OF MexY The resistance-nodulation-cell division (RND) components of RND-type tripartite multidrug efflux pumps determine substrate specificity (e.g., Srikumar et al, 1997; Eda et al, 2003); we focused on the structure and function of MexY rather than MexX or OprM

Summary

MexXY multidrug efflux system of Pseudomonas aeruginosa

Anti-pseudomonas aminoglycosides, such as amikacin and tobramycin, are used in the treatment of Pseudomonas aeruginosa infections Their use is linked to the development of resistance. The MexXY multidrug efflux system has been comprehensively studied, and numerous reports of laboratory and clinical isolates have been published. This system has been increasingly recognized as one of the primary determinants of aminoglycoside resistance in P. aeruginosa. We summarize the properties (e.g., discovery, mechanism, gene expression, clinical significance) of the P. aeruginosa MexXY pump and other aminoglycoside efflux pumps such as AcrD of Escherichia coli, AmrAB-OprA of B. pseudomallei, and AdeABC of Acinetobacter baumannii.

INTRODUCTION

Findings

RND OMF