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.
Highlights
Porphyromonas gingivalis is a keystone bacterial pathogen of chronic periodontitis
Similar to P. gingivalis HmuY haemophore[28,29], Haem uptake system protein A (HusA) is detected attached on the outer membrane and released into the extracellular milieu under iron-limited conditions
Disabling the husA gene significantly impairs the capacity of P. gingivalis to survive within epithelial cells
Summary
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. 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. HusA binds to a variety of porphyrins, including abiotic deuteroporphyrin IX (DPIX), with significantly higher affinities than it binds to haem We use this property to deliver a deuteroporphyrin-metronidazole antibiotic as a “Trojan horse”, resulting in effective elimination of intracellular P. gingivalis
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