title: Amino acid-linked porphyrin-nitroimidazole antibiotics targeting Porphyromonas gingivalis.
abstract: 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.
authors.affiliation: Institute of Dental Research, Westmead Millennium Institute and Centre for Oral Health, Westmead, NSW 2145, Australia.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Dingsdag
authors.forename: Benjamin C-M
authors.initials: BC
authors.lastname: Yap
authors.forename: Neil
authors.initials: N
authors.lastname: Hunter
authors.forename: Maxwell J
authors.initials: MJ
authors.lastname: Crossley
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D008239:Lysine / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D009593:Nitroimidazoles / Q000737:chemistry*; D011166:Porphyrins / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D016966:Porphyromonas gingivalis / Q000187:drug effects*; D011392:Proline / Q000737:chemistry*; D012995:Solubility; D014867:Water / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D009593:Nitroimidazoles; D011166:Porphyrins; D014867:Water; D011392:Proline; D008239:Lysine