Oral Presentation Australian Society for Microbiology Annual Scientific Meeting 2019

Novel antimicrobial strategy by arming the essential nutrient for the targeted elimination of Porphyromonas gingivalis (#197)

Jinlong Gao 1
  1. The University of Sydney, Westmead, NSW, Australia

The Gram-negative anaerobe Porphyromonas gingivalis is a “keystone” pathogen in chronic periodontitis whereby the capacity of the organism to dysregulate local host defence mechanisms drives a shift in the dental plaque microbiota towards dysbiosis. Subsequent host response against the dysbiotic microflora results in progressive destruction of supporting structures of the teeth and eventual tooth loss. Experimental models and epidemiological data show that P. gingivalis infection may also contribute to systemic pathology such as atheroma formation and rheumatoid arthritis. Critically, one strategy P. gingivalis employs to avoid immune surveillance is by invading oral epithelial cells. High levels of intracellular P. gingivalis can be recovered from the oral cavity of subjects with periodontitis, and this provides a reservoir for recurrent infection after therapy. Effective targeting of intracellular P. gingivalis is therefore an important aspect of enhanced antimicrobial therapy. Characteristically, P. gingivalis is unable to synthesise the porphyrin macrocycle and relies on exogenous porphyrin, most apparently as haem from host sources. Here we show that under iron-limited conditions prevailing in tissue environments, P. gingivalis expresses a haemophore-like protein, HusA, to mediate uptake of essential porphyrin as well as survival within epithelial cells. The solution structure of HusA presents the haem binding site as a shallow hydrophobic pocket on the a-helical structure but without evidence for coordination of prosthetic iron. This unusual binding feature also accommodates a variety of porphyrins including abiotic deuteroporphyrin IX, with higher binding affinity than for haem. We further show that an amino acid linked deuteroporphyrin-metronidazole conjugate with restricted antimicrobial specificity could function as a “Trojan horse” linked to HusA binding, for effective killing of intracellular P. gingivalis.