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Infect. Immun. doi:10.1128/IAI.01718-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Mechanisms of Decreased Susceptibility to -defensins by Treponema denticola

Departments of Pathobiology, Oral Biology, and Medicine, University of Washington, Seattle, Washington 98195

^* To whom correspondence should be addressed. Email: lukehart{at}u.washington.edu.

	Abstract

Treponema denticola, a periodontal pathogen, is relatively resistant to human beta-defensins (hD), small cationic antimicrobial peptides produced by a number of cells, including the gingival epithelium. We have previously demonstrated, using two independent methods, that T. denticola proteases are not responsible for decreased vulnerability to defensins. In this study, we confirm that the major outer membrane protease, dentilisin, is not responsible for T. denticola insensitivity to defensins, and explore 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 demonstrate increased susceptibility to hD-2, suggesting that cloaking of the outer surface with host proteins is not involved in defensin resistance. Nonetheless, we demonstrate that T. denticola binds significantly less hD-2 and -3 as compared to susceptible organisms, 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 -defensins was investigated. Three inhibitors of bacterial ATP-binding cassette (ABC) efflux pumps had no effect on T. denticola's susceptibility to hD-2 or -3. In contrast, a proton motive force inhibitor, CCCP, increased susceptibility of T. denticola to killing by hD-3, demonstrating a potential role for efflux pumps (other than ABC pumps) in resistance to that 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 -defensins.

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