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

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Gao, J-L, Kwan, AH, Yammine, A, Zhou, X, Trewhella, J, Hugrass, BM, Collins, DAT, Horne, HJ ORCID: 0000-0002-1935-2378, Ye, P, Harty, D, Nguyen, K-A, Gell, DA ORCID: 0000-0003-0382-1181 and Hunter, N 2018 , 'Structural properties of a haemophore facilitate targeted elimination of the pathogen Porphyromonas gingivalis' , Nature Communications, vol. 9 , pp. 1-13 , doi: 10.1038/s41467-018-06470-0.

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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 Type: Article
Authors/Creators:Gao, J-L and Kwan, AH and Yammine, A and Zhou, X and Trewhella, J and Hugrass, BM and Collins, DAT and Horne, HJ and Ye, P and Harty, D and Nguyen, K-A and Gell, DA and Hunter, N
Keywords: haem, porphyromonas gingivalis
Journal or Publication Title: Nature Communications
Publisher: United Kingdom
ISSN: 2041-1723
DOI / ID Number: 10.1038/s41467-018-06470-0
Copyright Information:

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

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