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Infection and Immunity, December 2002, p. 6968-6975, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.6968-6975.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Attenuation of the Virulence of Porphyromonas gingivalis by Using a Specific Synthetic Kgp Protease Inhibitor

M. A. Curtis,1* J. Aduse Opoku,1 M. Rangarajan,1 A. Gallagher,1 J. A. C. Sterne,2 C. R. Reid,1 H. E. A. Evans,1 and B. Samuelsson3

MRC Molecular Pathogenesis Group, Medical Microbiology, Bart's and the London, Queen Mary's School of Medicine and Dentistry, London E1 2AA,1 Department of Social Medicine, University of Bristol, Bristol,2 Medivir, Cambridge, United Kingdom3

Received 21 February 2002/ Returned for modification 9 May 2002/ Accepted 22 July 2002

The Arg- and Lys-gingipains of Porphyromonas gingivalis are important virulence determinants in periodontal disease and may correspond to targets for immune- or drug-based treatment strategies. In this investigation we aimed to determine which of these enzymes represents the most promising molecular target for protease inhibitor-based therapy and to examine the effectiveness of the resultant compound in a murine virulence assay. Isogenic mutants with mutations in rgpA and rgpB (encoding Arg-gingipains) and in kgp (encoding Lys-gingipain) and a double mutant with mutations in rgpA and rgpB were prepared by using P. gingivalis W50. The virulence of these mutants indicated that Kgp is a promising drug target. Combinatorial chemistry was used to define the optimal substrate of Kgp, and from this information a specific slowly reversible inhibitor with a nanomolar Ki was designed and synthesized. Growth of P. gingivalis W50 in the presence of this compound resembled the phenotype of the kgp isogenic mutant; in both instances bacterial colonies failed to form pigment on blood agar, and only poor growth was obtained in a defined medium containing albumin as the sole protein source. Furthermore, pretreatment of the wild-type organism with the Kgp inhibitor led to a significant reduction in virulence in the murine assay. These data emphasize the conclusion that Kgp is an important factor for both nutrition and virulence of P. gingivalis and that inhibitors of this enzyme may have therapeutic potential for the control of P. gingivalis infections. Protease inhibitors may be a potentially novel class of antimicrobial agents with relevance to the control of other bacterial pathogens.

* Corresponding author. Mailing address: MRC Molecular Pathogenesis Group, Medical Microbiology, Bart's and the London, Queen Mary's School of Medicine and Dentistry, 32 Newark St., London E1 2AA, United Kingdom. Phone: 44 207 377 0444. Fax: 44 207 247 3428. E-mail: M.A.Curtis{at}qmul.ac.uk.

Editor: B. B. Finlay

Infection and Immunity, December 2002, p. 6968-6975, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.6968-6975.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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