PROJECT SUMMARY/ABSTRACT
Microbial interaction between Porphyromonas gingivalis (Pg) and Fusobacterium nucleatum (Fn) worsens
inflammation in periodontal disease (PD), promoting damage to connective tissues, alveolar bone resorption,
and tooth loss. Chronic PD also accelerates oral cancers and is a risk factor for multiple diseases. Nonsurgical
treatments for PD include mechanical debridement with or without broad-spectrum antibiotics. However, current
antibiotics for PD have drawbacks, including exacerbation of oral dysbiosis; intestinal dysbiosis, which is a risk
factor for microbiota shift diseases; and enriching the spread of antimicrobial resistance. We hypothesize that a
narrow-spectrum agent that selectively eliminates Pg or Pg and Fn would be a valuable adjunct to debridement.
Such agents could potentially decrease inflammation, making the periodontal environment more favorable for
colonization by healthy oral microbes. We will test this hypothesis by exploring the isoenzyme FabK as a drug
target for narrow-spectrum agents. FabK, enoyl-acyl carrier protein (ACP) reductase II, is a key enzyme in the
bacterial fatty acid synthesis pathway (FAS II) that catalyzes the elongation step of bacterial type II fatty acid
synthesis (FAS-II) to make lipids for membranes and virulence. Inhibition of FAS II causes a strong antibacterial
effect. Pg and Fn uniquely express the FabK isozyme, which is structurally and mechanistically distinct from
FabI and other enoyl-ACP reductase isozymes that are found in many other oral species. Our hypothesis is
backed by strong preliminary data supporting the essentiality of FabK to Pg and Fn, as FabK inhibitors stop their
growth. Our long-term goal is to establish a drug discovery platform for inhibitors of Pg and Fn FabK enzymes
to eliminate these organism(s) in PD and other oral diseases. The objectives of this application are to define the
characteristics for a suitable target product profile, by determining: 1) the cellular effect of FabK inhibition in
planktonic and biofilm communities (aim 1a); 2) in vivo druggability of FabK in chronic PD, based on efficacy of
known inhibitors (aim 1b); and 3) the structural and substrate requirements for inhibition and catalysis of Pg or
both Pg and Fn FabKs, which will guide the chemical expansion and optimization of future inhibitors (aim 2). We
anticipate the results will attain benchmarks for an advanced discovery program to develop drug candidates with
desirable antimicrobial, mechanistic, and chemical profiles to prevent and treat PD. Such technologies may also
have wider applications for PD-related systemic diseases. We also expect to advance knowledge of Pg and Fn
FAS-II lipid metabolism in PD and biochemical insights of FabK activity in these organisms.
