Amino acid-linked porphyrin-nitroimidazole antibiotics targeting Porphyromonas gingivalis

Org Biomol Chem. 2015 Jan 7;13(1):98-109. doi: 10.1039/c4ob01841a.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology
  • Bacterial Outer Membrane Proteins / metabolism
  • Cell Line
  • Drug Design*
  • Humans
  • Lysine / chemistry*
  • Microbial Sensitivity Tests
  • Nitroimidazoles / chemistry*
  • Porphyrins / chemical synthesis
  • Porphyrins / chemistry*
  • Porphyrins / metabolism
  • Porphyrins / pharmacology*
  • Porphyromonas gingivalis / drug effects*
  • Proline / chemistry*
  • Solubility
  • Water / chemistry

Substances

  • Anti-Bacterial Agents
  • Bacterial Outer Membrane Proteins
  • Nitroimidazoles
  • Porphyrins
  • Water
  • Proline
  • Lysine