Peptide-Based Inhibitors of Fimbrial Biogenesis in Porphyromonas gingivalis

Abstract

Periodontitis is a progressive inflammatory disease that affects roughly half of American adults. Colonization of the oral cavity by the Gram-negative bacterial pathogen <i>Porphyromonas gingivalis</i> is a key event in the initiation and development of periodontal disease. Adhesive surface structures termed fimbriae (pili) mediate interactions of <i>P. gingivalis</i> with other bacteria and with host cells throughout the course of disease. The <i>P. gingivalis</i> fimbriae are assembled via a novel mechanism that involves proteolytic processing of lipidated precursor subunits and their subsequent polymerization on the bacterial surface. Given their extracellular assembly mechanism and central roles in pathogenesis, the <i>P. gingivalis</i> fimbriae are attractive targets for anti-infective therapeutics to prevent or treat periodontal disease. Here we confirm that conserved sequences in the N and C termini of the Mfa1 fimbrial subunit protein perform critical roles in subunit polymerization. We show that treatment of <i>P. gingivalis</i> with peptides corresponding to the conserved C-terminal region inhibits the extracellular assembly of Mfa fimbriae on the bacterial surface. We also show that peptide treatment interferes with the function of Mfa fimbriae by reducing <i>P. gingivalis</i> adhesion to <i>Streptococcus gordonii</i> in a dual-species biofilm model. Finally, we show that treatment of bacteria with similar peptides inhibits extracellular polymerization of the Fim fimbriae, which are also expressed by <i>P. gingivalis</i> These results support a donor strand-based assembly mechanism for the <i>P. gingivalis</i> fimbriae and demonstrate the feasibility of using extracellular peptides to disrupt the biogenesis and function of these critical periodontal disease virulence factors.