Amino acid-linked porphyrin-nitroimidazole antibiotics targeting Porphyromonas gingivalis. Issue 1 (22nd October 2014)

• Record Type: Journal Article
• Authors: Dingsdag, Simon A.; Yap, Benjamin C-M.; Hunter, Neil; Crossley, Maxwell J.
• Is Part Of: Organic & biomolecular chemistry. Volume 13:Issue 1(2015)
• Page Start: 98
• Page End: 109
• Publication Date: 2014-10-22
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/c4ob01841a
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : Amino acid-linked porphyrin-nitroimidazole adducts, as potent as metronidazole, are highly selective for 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 ofl -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.