Porphyromonas gingivalis, one of the causative agents of adult periodontitis, develops biofilm microcolonies on substrata of Streptococcus gordonii but not on Streptococcus mutans. P. gingivalis genome microarrays were used to identify genes differentially regulated during accretion of P. gingivalis in heterotypic biofilms with S. gordonii. Thirty-three genes showed up-or downregulation by array analysis, and differential expression was confirmed by quantitative reverse transcription-PCR. The functions of the regulated genes were predominantly related to metabolism and energy production. In addition, many of the genes have no current known function. The roles of two upregulated genes, ftsH (PG0047) encoding an ATP-dependent zinc metallopeptidase and ptpA (PG1641) encoding a putative tyrosine phosphatase, were investigated further by mutational analysis. Strains with mutations in these genes developed more abundant biofilms with S. gordonii than the parental strain developed. ftsH and ptpA may thus participate in a regulatory network that constrains P. gingivalis accumulation in heterotypic biofilms. This study provided a global analysis of P. gingivalis transcriptional responses in an oral microbial community and also provided insight into the regulation of heterotypic biofilm development.Periodontal diseases are a group of infections characterized by destruction of the supporting structures of the teeth. Porphyromonas gingivalis is a gram-negative anaerobe that is an important pathogen in severe manifestations of these diseases (15,41). With regard to the disease process, the primary ecological niche of P. gingivalis is in the subgingival area, where toxic products, such as proteases, can readily access the periodontal tissues. However, initial colonization of the oral cavity by P. gingivalis involves attachment to sites remote from the subgingival area, including the supragingival tooth surface (28,39,43,47,57,58). Indeed, introduction of P. gingivalis into the mouths of human volunteers results in localization almost exclusively on supragingival surfaces (39). The bacterial inhabitants of the supragingival tooth surface comprise a complex multispecies biofilm (42), and numerous in vitro studies have demonstrated the ability of P. gingivalis to attach to common constituents of the supragingival biofilm, including Actinomyces species and oral streptococci (12, 35). The molecular basis of P. gingivalis adhesion to Streptococcus gordonii has been investigated in some detail and has been shown to be multivalent (3,4,23,24,45). The P. gingivalis long fimbriae (FimA) bind to glyceraldehyde-3-phosphate dehydrogenase present on the streptococcal surface (27). In addition, the P. gingivalis short fimbriae (Mfa) engage the streptococcal SspA/B (antigen I/II) adhesins (33) through an approximately 80-amino-acid binding epitope of SspA/B termed BAR (11). Coadhesion mediated through these effectors is required for P. gingivalis to accumulate in a heterotypic biofilm with S. gordonii (23).In contrast to the synergistic rela...