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Infection and Immunity, May 2007, p. 2307-2315, Vol. 75, No. 5
0019-9567/07/$08.00+0     doi:10.1128/IAI.01718-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Mechanisms of Decreased Susceptibility to ß-Defensins by Treponema denticola{triangledown}

Catherine A. Brissette1,2 and Sheila A. Lukehart1,2,3*

Departments of Pathobiology,1 Oral Biology,2 Medicine, University of Washington, Seattle, Washington 981953

Received 26 October 2006/ Returned for modification 5 December 2006/ Accepted 14 February 2007

Treponema denticola, a periodontal pathogen, is relatively resistant to human beta-defensins, which are small cationic antimicrobial peptides produced by a number of cells, including the gingival epithelium. Using two independent methods, we previously demonstrated that T. denticola proteases are not responsible for decreased vulnerability to defensins. In this study, we confirmed that the major outer membrane protease, dentilisin, is not responsible for T. denticola insensitivity to defensins and examined several other possible mechanisms, including reduced binding to the bacterial surface and efflux pump activity. It has been suggested that some bacteria mask their surfaces with serum proteins. T. denticola grown in a serum-free medium did not exhibit increased susceptibility to human beta-defensin 2 and 3 (hßD-2 and hßD-3, respectively), suggesting that cloaking of the outer surface with host proteins is not involved in defensin resistance. Nonetheless, we demonstrated that T. denticola binds significantly less hßD-2 and -3 than susceptible organisms bind, suggesting that the unusual outer membrane composition of T. denticola may discourage cationic peptide binding. Efflux pumps have been shown to mediate resistance to antibiotics and cationic peptides in other bacteria, and their role in T. denticola's relative resistance to ß-defensins was investigated. Three inhibitors of bacterial ATP-binding cassette (ABC) efflux pumps had no effect on T. denticola's susceptibility to hßD-2 or -3. In contrast, a proton motive force inhibitor, carbonyl cyanide 3-chlorophenylhydrazone, increased the susceptibility of T. denticola to killing by hßD-3, demonstrating a potential role for efflux pumps (other than ABC pumps) in resistance to this peptide. Our data suggest that the combination of decreased defensin binding and efflux of any peptide which enters the cytoplasm may explain T. denticola's relative resistance to human beta-defensins.

* Corresponding author. Mailing address: Department of Medicine, Box 359779, Harborview Medical Center, 325 Ninth Avenue, Seattle, WA 98104. Phone: (206) 341-5362. Fax: (206) 341-5363. E-mail: lukehart{at}u.washington.edu

{triangledown} Published ahead of print on 26 February 2007.

Editor: V. J. DiRita

Infection and Immunity, May 2007, p. 2307-2315, Vol. 75, No. 5
0019-9567/07/$08.00+0     doi:10.1128/IAI.01718-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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