Structural properties of a haemophore facilitate targeted elimination of the pathogen Porphyromonas gingivalis

Jin-Long Gao (), Ann H. Kwan, Anthony Yammine, Xiaoyan Zhou, Jill Trewhella, Barbara M. Hugrass, Daniel A. T. Collins, James Horne, Ping Ye, Derek Harty, Ky-Anh Nguyen, David A. Gell () and Neil Hunter
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Jin-Long Gao: The University of Sydney
Ann H. Kwan: School of Life and Environmental Sciences and Sydney Nano, The University of Sydney
Anthony Yammine: School of Life and Environmental Sciences and Sydney Nano, The University of Sydney
Xiaoyan Zhou: The University of Sydney
Jill Trewhella: School of Life and Environmental Sciences and Sydney Nano, The University of Sydney
Barbara M. Hugrass: School of Medicine, The University of Tasmania
Daniel A. T. Collins: School of Medicine, The University of Tasmania
James Horne: Central Science Laboratory, The University of Tasmania
Ping Ye: Westmead Centre for Oral Health
Derek Harty: Westmead Centre for Oral Health
Ky-Anh Nguyen: The University of Sydney
David A. Gell: School of Medicine, The University of Tasmania
Neil Hunter: The University of Sydney

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Porphyromonas gingivalis is a keystone bacterial pathogen of chronic periodontitis. P. gingivalis is unable to synthesise the porphyrin macrocycle and relies on exogenous porphyrin, including haem or haem biosynthesis intermediates from host sources. We show that under the iron-limited conditions prevailing in tissue environments, P. gingivalis expresses a haemophore-like protein, HusA, to mediate the uptake of essential porphyrin and support pathogen survival within epithelial cells. The structure of HusA, together with titration studies, mutagenesis and in silico docking, show that haem binds in a hydrophobic groove on the α-helical structure without the typical iron coordination seen in other haemophores. This mode of interaction allows HusA to bind to a variety of abiotic and metal-free porphyrins with higher affinities than to haem. We exploit this unusual porphyrin-binding activity of HusA to target a prototypic deuteroporphyrin-metronidazole conjugate with restricted antimicrobial specificity in a Trojan horse strategy that effectively kills intracellular P. gingivalis.

Date: 2018
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DOI: 10.1038/s41467-018-06470-0

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