Binaphthyl-1,2,3-triazole peptidomimetics with activity against Clostridium difficile and other pathogenic bacteria

Steven M Wales, Katherine A Hammer, Amy McKarral King, Andrew J Tague, Dena Lyras, Thomas V Riley, Paul A Keller, Stephen J Pyne

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Clostridium difficile (C. difficile) is a problematic Gram positive bacterial pathogen causing moderate to severe gastrointestinal infections. Based on a lead binaphthyl-tripeptide dicationic antimicrobial, novel mono-, di- and tri-peptidomimetic analogues targeting C. difficile were designed and synthesized incorporating one, two or three d-configured cationic amino acid residues, with a common 1,2,3-triazole ester isostere at the C-terminus. Copper- and ruthenium-click chemistry facilitated the generation of a 46 compound library for in vitro bioactivity assays, with structure-activity trends over the largest compound subset revealing a clear advantage to triazole-substitution with a linear or branched hydrophobic group. The most active compounds were dicationic-dipeptides where the triazole was substituted with a 4- or 5-cyclohexylmethyl or 4,5-diphenyl moiety, providing MICs of 4 mug mL(-1) against three human isolates of C. difficile. Further biological screening revealed significant antimicrobial activity for several compounds against other common bacterial pathogens, both Gram positive and negative, including S. aureus (MICs >/=2 mug mL(-1)), S. pneumoniae (MICs >/=1 mug mL(-1)), E. coli (MICs >/=4 mug mL(-1)), A. baumannii (MICs >/=4 mug mL(-1)) and vancomycin-resistant E. faecalis (MICs >/=4 mug mL(-1)).
Original languageEnglish
Pages (from-to)5743 - 5756
Number of pages14
JournalOrganic and Biomolecular Chemistry
Volume13
Issue number20
DOIs
Publication statusPublished - 2015

Cite this

Wales, Steven M ; Hammer, Katherine A ; King, Amy McKarral ; Tague, Andrew J ; Lyras, Dena ; Riley, Thomas V ; Keller, Paul A ; Pyne, Stephen J. / Binaphthyl-1,2,3-triazole peptidomimetics with activity against Clostridium difficile and other pathogenic bacteria. In: Organic and Biomolecular Chemistry. 2015 ; Vol. 13, No. 20. pp. 5743 - 5756.
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abstract = "Clostridium difficile (C. difficile) is a problematic Gram positive bacterial pathogen causing moderate to severe gastrointestinal infections. Based on a lead binaphthyl-tripeptide dicationic antimicrobial, novel mono-, di- and tri-peptidomimetic analogues targeting C. difficile were designed and synthesized incorporating one, two or three d-configured cationic amino acid residues, with a common 1,2,3-triazole ester isostere at the C-terminus. Copper- and ruthenium-click chemistry facilitated the generation of a 46 compound library for in vitro bioactivity assays, with structure-activity trends over the largest compound subset revealing a clear advantage to triazole-substitution with a linear or branched hydrophobic group. The most active compounds were dicationic-dipeptides where the triazole was substituted with a 4- or 5-cyclohexylmethyl or 4,5-diphenyl moiety, providing MICs of 4 mug mL(-1) against three human isolates of C. difficile. Further biological screening revealed significant antimicrobial activity for several compounds against other common bacterial pathogens, both Gram positive and negative, including S. aureus (MICs >/=2 mug mL(-1)), S. pneumoniae (MICs >/=1 mug mL(-1)), E. coli (MICs >/=4 mug mL(-1)), A. baumannii (MICs >/=4 mug mL(-1)) and vancomycin-resistant E. faecalis (MICs >/=4 mug mL(-1)).",
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Binaphthyl-1,2,3-triazole peptidomimetics with activity against Clostridium difficile and other pathogenic bacteria. / Wales, Steven M; Hammer, Katherine A; King, Amy McKarral; Tague, Andrew J; Lyras, Dena; Riley, Thomas V; Keller, Paul A; Pyne, Stephen J.

In: Organic and Biomolecular Chemistry, Vol. 13, No. 20, 2015, p. 5743 - 5756.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Binaphthyl-1,2,3-triazole peptidomimetics with activity against Clostridium difficile and other pathogenic bacteria

AU - Wales, Steven M

AU - Hammer, Katherine A

AU - King, Amy McKarral

AU - Tague, Andrew J

AU - Lyras, Dena

AU - Riley, Thomas V

AU - Keller, Paul A

AU - Pyne, Stephen J

PY - 2015

Y1 - 2015

N2 - Clostridium difficile (C. difficile) is a problematic Gram positive bacterial pathogen causing moderate to severe gastrointestinal infections. Based on a lead binaphthyl-tripeptide dicationic antimicrobial, novel mono-, di- and tri-peptidomimetic analogues targeting C. difficile were designed and synthesized incorporating one, two or three d-configured cationic amino acid residues, with a common 1,2,3-triazole ester isostere at the C-terminus. Copper- and ruthenium-click chemistry facilitated the generation of a 46 compound library for in vitro bioactivity assays, with structure-activity trends over the largest compound subset revealing a clear advantage to triazole-substitution with a linear or branched hydrophobic group. The most active compounds were dicationic-dipeptides where the triazole was substituted with a 4- or 5-cyclohexylmethyl or 4,5-diphenyl moiety, providing MICs of 4 mug mL(-1) against three human isolates of C. difficile. Further biological screening revealed significant antimicrobial activity for several compounds against other common bacterial pathogens, both Gram positive and negative, including S. aureus (MICs >/=2 mug mL(-1)), S. pneumoniae (MICs >/=1 mug mL(-1)), E. coli (MICs >/=4 mug mL(-1)), A. baumannii (MICs >/=4 mug mL(-1)) and vancomycin-resistant E. faecalis (MICs >/=4 mug mL(-1)).

AB - Clostridium difficile (C. difficile) is a problematic Gram positive bacterial pathogen causing moderate to severe gastrointestinal infections. Based on a lead binaphthyl-tripeptide dicationic antimicrobial, novel mono-, di- and tri-peptidomimetic analogues targeting C. difficile were designed and synthesized incorporating one, two or three d-configured cationic amino acid residues, with a common 1,2,3-triazole ester isostere at the C-terminus. Copper- and ruthenium-click chemistry facilitated the generation of a 46 compound library for in vitro bioactivity assays, with structure-activity trends over the largest compound subset revealing a clear advantage to triazole-substitution with a linear or branched hydrophobic group. The most active compounds were dicationic-dipeptides where the triazole was substituted with a 4- or 5-cyclohexylmethyl or 4,5-diphenyl moiety, providing MICs of 4 mug mL(-1) against three human isolates of C. difficile. Further biological screening revealed significant antimicrobial activity for several compounds against other common bacterial pathogens, both Gram positive and negative, including S. aureus (MICs >/=2 mug mL(-1)), S. pneumoniae (MICs >/=1 mug mL(-1)), E. coli (MICs >/=4 mug mL(-1)), A. baumannii (MICs >/=4 mug mL(-1)) and vancomycin-resistant E. faecalis (MICs >/=4 mug mL(-1)).

UR - http://www.ncbi.nlm.nih.gov/pubmed/25901416

U2 - 10.1039/c5ob00576k

DO - 10.1039/c5ob00576k

M3 - Article

VL - 13

SP - 5743

EP - 5756

JO - Organic and Biomolecular Chemistry

JF - Organic and Biomolecular Chemistry

SN - 1477-0520

IS - 20

ER -