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Antimicrobial Agents and Chemotherapy, July 1999, p. 1719-1724, Vol. 43, No. 7
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Reversal of Tetracycline Resistance Mediated by Different Bacterial Tetracycline Resistance Determinants by an Inhibitor of the Tet(B) Antiport Protein

Mark L. Nelson1,2 and Stuart B. Levy1,2,3,*

Center for Adaptation Genetics and Drug Resistance1 and Departments of Molecular Biology and Microbiology2 and of Medicine,3 Tufts University School of Medicine, Boston, Massachusetts 02111

Received 10 December 1998/Returned for modification 1 February 1999/Accepted 21 April 1999

Active efflux is a useful strategy by which bacteria evade growth inhibition by antibiotics. Certain semisynthetic tetracycline (TC) analogs, substituted at the 13th carbon at C-6 on ring C of the TC molecule, blocked TC efflux as revealed in everted membrane vesicles from class B TC-resistant (Tcr) Escherichia coli (M. L. Nelson, B. H. Park, J. S. Andrews, V. A. Georgian, R. C. Thomas, and S. B. Levy, J. Med. Chem. 36:370-377, 1993). A representative C-13-substituted analog, 13-cyclopentylthio-5-OH-TC (13-CPTC), was shown to competitively inhibit TC translocation by the Tet(B) protein, blocking the uptake of TC into vesicles and therefore the efflux of TC from whole cells. Against Tcr E. coli, 13-CPTC, when used in combination with doxycycline, produced synergistic inhibition of growth. 13-CPTC was shown to increase the uptake of [3H]TC into the resistant cells. 13-CPTC alone was a potent growth inhibitor against TC-susceptible (Tcs) and Tcr Staphylococcus aureus and enterococci specifying class K or class L efflux-dependent TC resistance mechanisms or, unexpectedly, the class M ribosomal protection mechanism. These findings indicate that derivatives of TC, identified by their ability to block the Tet(B) efflux protein, can restore TC activity against Tcr bacteria bearing either of the two known resistance mechanisms. Blocking drug efflux and increasing intracellular drug concentrations constitute an effective approach to reversing TC resistance and may be generally applicable to other antibiotics rendered ineffective by efflux proteins.

* Corresponding author. Mailing address: Center for Adaptation Genetics and Drug Resistance, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111. Phone: (617) 636-6764. Fax: (617) 636-0458. E-mail: slevy{at}opal.tufts.edu.

Antimicrobial Agents and Chemotherapy, July 1999, p. 1719-1724, Vol. 43, No. 7
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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