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Antimicrobial Agents and Chemotherapy, March 2005, p. 1017-1022, Vol. 49, No. 3
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.3.1017-1022.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Influence of Transcriptional Activator RamA on Expression of Multidrug Efflux Pump AcrAB and Tigecycline Susceptibility in Klebsiella pneumoniae

Alexey Ruzin,1* Melissa A. Visalli ,1,{dagger},{ddagger} David Keeney,1,{dagger} and Patricia A. Bradford1

Wyeth Research, Pearl River, New York1

Received 4 June 2004/ Returned for modification 28 August 2004/ Accepted 3 November 2004

Tigecycline is an expanded broad-spectrum antibacterial agent that is active against many clinically relevant species of bacterial pathogens, including Klebsiella pneumoniae. The majority of K. pneumoniae isolates are fully susceptible to tigecycline; however, a few strains that have decreased susceptibility have been isolated. One isolate, G340 (for which the tigecycline MIC is 4 µg/ml and which displays a multidrug resistance [MDR] phenotype), was selected for analysis of the mechanism for this decreased susceptibility by use of transposon mutagenesis with IS903{phi}kan. A tigecycline-susceptible mutant of G340, GC7535, was obtained (tigecycline MIC, 0.25 µg/ml). Analysis of the transposon insertion mapped it to ramA, a gene that was previously identified to be involved in MDR in K. pneumoniae. For GC7535, the disruption of ramA led to a 16-fold decrease in the MIC of tigecycline and also a suppression of MDR. Trans-complementation with plasmid-borne ramA restored the original parental phenotype of decreased susceptibility to tigecycline. Northern blot analysis revealed a constitutive overexpression of ramA that correlated with an increased expression of the AcrAB transporter in G340 compared to that in tigecycline-susceptible strains. Laboratory mutants of K. pneumoniae with decreased susceptibility to tigecycline could be selected at a frequency of approximately 4 x 10–8. These results suggest that ramA is associated with decreased tigecycline susceptibility in K. pneumoniae due to its role in the expression of the AcrAB multidrug efflux pump.

* Corresponding author. Mailing address: Wyeth Research, Department of Infectious Disease, 401 North Middletown Rd., Bldg. 200, Rm. 3219, Pearl River, NY 10965. Phone: (845) 602-4592. Fax: (845) 602-5671. E-mail: ruzina{at}wyeth.com.

{dagger} M.A.V. and D.K. contributed equally to the present study.

{ddagger} Present address: Fort Wayne, Ind.

Antimicrobial Agents and Chemotherapy, March 2005, p. 1017-1022, Vol. 49, No. 3
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.3.1017-1022.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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