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

Citation

Gao, J-L and Kwan, AH and Yammine, A and Zhou, X and Trewhella, J and Hugrass, BM and Collins, DAT and Horne, J and Ye, P and Harty, D and Nguyen, K-A and Gell, DA and Hunter, N, Structural properties of a haemophore facilitate targeted elimination of the pathogen Porphyromonas gingivalis, Nature Communications, 9 Article 4097. ISSN 2041-1723 (2018) [Refereed Article]


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Copyright Statement

2018 The Authors. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/

DOI: doi:10.1038/s41467-018-06470-0

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.

Item Details

Item Type:Refereed Article
Keywords:haem, porphyromonas gingivalis, haemophore, chronic periodontitis, porphyrin macrocycle, HusA
Research Division:Biological Sciences
Research Group:Biochemistry and Cell Biology
Research Field:Structural Biology (incl. Macromolecular Modelling)
Objective Division:Expanding Knowledge
Objective Group:Expanding Knowledge
Objective Field:Expanding Knowledge in the Biological Sciences
Author:Collins, DAT (Mr Daniel Collins)
Author:Horne, J (Dr James Horne)
Author:Gell, DA (Dr David Gell)
ID Code:128724
Year Published:2018
Deposited By:Medicine (Discipline)
Deposited On:2018-10-10
Last Modified:2018-12-11
Downloads:0

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