Protegrins, small peptides (1900 to 2160 daltons) isolated from porcine leukocytes, are bactericidal against a broad range of medical pathogens in vitro under conditions which reflect the extracellular milieu. The purpose of this study was to determine whether Gram-negative, facultative periodontal pathogens were sensitive to the protegrins. Synthetic L- and D-enantiomers of protegrin 1 (PG-1 and D-PG-1, respectively), and L-enantiomers of protegrins 2, 3, and 5 (PG-2, PG-3, and PG-5) were tested against Actinobacillus actinomycetemcomitans (three strains) and Capnocytophaga spp. (three strains). Strains of both A. actinomycetemcomitans and Capnocytophaga spp. were sensitive to PG-1, and exhibited ED99 (dose at which 99% killing was observed after 1 hr at 37 degrees C) of 0.5 to 3 microg/mL and 4 to 19 microg/mL, respectively. The D-form and the L-form were equally effective. Serum (above 5% v/v) inhibited the bactericidal effects of 10 microg/mL PG-1, but the inhibitory effect was overcome by concentrations of PG-1 at 100 microg/mL. Different patterns of sensitivity were observed when the effects of PG-1, D-PG-1, PG-2, PG-3, and PG-5 were compared against A. actinomycetemcomitans and the Capnocytophaga. We conclude that protegrins may be useful antimicrobial agents in therapy against periodontal infections.