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Issue 1, 2015
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Amino acid-linked porphyrin-nitroimidazole antibiotics targeting Porphyromonas gingivalis

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The periodontal pathogen Porphyromonas gingivalis requires porphyrin supplementation for growth. Previously, in order to inhibit P. gingivalis growth, we synthesised very effective ‘Trojan horse’ ester and amide-linked deuterporphyrin-nitroimidazole (DPIX-Nim) adducts that exploited this requirement to transport metronidazole-derived antibiotics with excellent antimicrobial selectivity and recognition by the HA2 porphyrin binding site. Herein, in the context of developing topical agents to target P. gingivalis, L-amino acids are incorporated into adducts as linkers to improve uptake. Ten 13- and 17-propionic amide regioisomers of L-amino acid-linked deuterporphyrin-nitroimidazole adducts were synthesised using a peptide coupling approach. DPIX-Lys regioisomers without attached nitroimidazole were also synthesised as comparison compounds. All the porphyrin adducts bound (Kd50 7 to 20 nM) to a recombinant HA2 receptor with similar binding affinity to haem, except the lysine-proline linked DPIX-Lys(Boc)Pro-Nim adducts (Kd50 300 nM) and the DPIX-Lys(Nim)-Nim adducts (Kd50 200 nM), both of which have large appended groups. DPIX-Lys(Boc)-Nim, DPIX-Lys(OH)-Nim, and DPIX-Pro-Nim adducts were shown to be very effective against P. gingivalis. DPIX-Lys(Boc)Pro-Nim adducts and DPIX-Lys(Nim)-Nim adducts showed weak activity. Importantly, DPIX-Lys(Boc)-Nim adducts were selective for P. gingivalis and, unlike metronidazole, did not kill a range of other anaerobic bacteria isolated from the human gastrointestinal tract.

Graphical abstract: Amino acid-linked porphyrin-nitroimidazole antibiotics targeting Porphyromonas gingivalis

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The article was received on 29 Aug 2014, accepted on 07 Oct 2014 and first published on 22 Oct 2014

Article type: Paper
DOI: 10.1039/C4OB01841A
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Citation: Org. Biomol. Chem., 2015,13, 98-109

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    Amino acid-linked porphyrin-nitroimidazole antibiotics targeting Porphyromonas gingivalis

    S. A. Dingsdag, B. C-M. Yap, N. Hunter and M. J. Crossley, Org. Biomol. Chem., 2015, 13, 98
    DOI: 10.1039/C4OB01841A

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