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Antimicrobial Agents and Chemotherapy, March 2003, p. 1101-1111, Vol. 47, No. 3
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.3.1101-1111.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Aminoglycoside Efflux in Pseudomonas aeruginosa: Involvement of Novel Outer Membrane Proteins

James T. H. Jo, Fiona S. L. Brinkman, and Robert E. W. Hancock*

Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3

Received 19 July 2002/ Returned for modification 25 November 2002/ Accepted 20 December 2002

The expression of tripartite multidrug efflux pumps such as MexA-MexB-OprM in Pseudomonas aeruginosa contributes to intrinsic resistance to a wide variety of antimicrobials, including ß-lactams, chloramphenicol, macrolides, quinolones, and tetracycline. The MexX-MexY linker-pump combination has been shown to be involved in intrinsic resistance to aminoglycosides, but the identity of the cognate outer membrane channel component remains under debate. Fourteen uncharacterized OprM homologs identified in the genome of P. aeruginosa were examined as candidates for this role by assessing the minimum inhibitory concentrations (MICs) of aminoglycosides in P. aeruginosa strain PAK knockout mutants lacking the corresponding genes. Insertional inactivation of OpmG, OpmI, and OpmH resulted in decreases of various degrees in the MICs of streptomycin, kanamycin, and gentamicin. When reintroduced into P. aeruginosa on multicopy plasmids, OpmG was able to complement the susceptibility of an opmG::miniTn5 mutant; however, cloned opmH, the proposed ortholog of Escherichia coli tolC according to our phylogenetic analysis, was able to only partially complement the opmH::miniTn5 mutant. Mini-microarray hybridization analysis demonstrated that opmG disruption does not affect expression of OpmI or OpmH (ruling out such indirect effects on aminoglycoside resistance); however, opmH disruption did have possible effects on expression of OpmG and OpmI. Based on the data, we propose that OpmG is a major outer membrane efflux channel involved in aminoglycoside efflux in P. aeruginosa PAK and that OpmI, its most related paralog, may share an overlapping function.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada V6T 1Z3. Phone: (604) 822-2682. Fax: (604) 822-6041. E-mail: bob{at}cmdr.ubc.ca.

Antimicrobial Agents and Chemotherapy, March 2003, p. 1101-1111, Vol. 47, No. 3
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.3.1101-1111.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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