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Antimicrobial Agents and Chemotherapy, May 2008, p. 1677-1685, Vol. 52, No. 5
0066-4804/08/$08.00+0     doi:10.1128/AAC.01644-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Efflux Pump Inhibitor Reserpine Selects Multidrug-Resistant Streptococcus pneumoniae Strains That Overexpress the ABC Transporters PatA and PatB{triangledown} ,{dagger}

Mark I. Garvey and Laura J. V. Piddock*

Antimicrobial Agents Research Group, Division of Immunity and Infection, The Medical School, University of Birmingham, Birmingham, United Kingdom B15 2TT

Received 21 December 2007/ Returned for modification 25 January 2008/ Accepted 29 February 2008

One way to combat multidrug-resistant microorganisms is the use of efflux pump inhibitors (EPIs). Spontaneous mutants resistant to the EPI reserpine selected from Streptococcus pneumoniae NCTC 7465 and R6 at a frequency suggestive of a single mutational event were also multidrug resistant. No mutations in pmrA (which encodes the efflux protein PmrA) were detected, and the expression of pmrA was unaltered in all mutants. In the reserpine-resistant multidrug-resistant mutants, the overexpression of both patA and patB, which encode ABC transporters, was associated with accumulation of low concentrations of antibiotics and dyes. The addition of sodium orthovanadate, an inhibitor of ABC efflux pumps, or the insertional inactivation of either gene restored wild-type antibiotic susceptibility and wild-type levels of accumulation. Only when patA was insertionally inactivated were both multidrug resistance and reserpine resistance lost. Strains in which patA was insertionally inactivated grew significantly more slowly than the wild type. These data indicate that the overexpression of both patA and patB confers multidrug resistance in S. pneumoniae but that only patA is involved in reserpine resistance. The selection of reserpine-resistant multidrug-resistant pneumococci has implications for analogous systems in other bacteria or in cancer.

* Corresponding author. Mailing address: Antimicrobial Agents Research Group, Division of Immunity and Infection, The Medical School, University of Birmingham, Birmingham, United Kingdom B15 2TT. Phone: 0121-414-6966. Fax: 0121-414-6819. E-mail: l.j.v.piddock{at}bham.ac.uk

{triangledown} Published ahead of print on 24 March 2008.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, May 2008, p. 1677-1685, Vol. 52, No. 5
0066-4804/08/$08.00+0     doi:10.1128/AAC.01644-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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