Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles targeting Clostridioides (Clostridium) difficile: Synthesis, antibacterial evaluation and an in vivo C. difficile infection model

Andrew J. Tague, Papanin Putsathit, Melanie L. Hutton, Katherine A. Hammer, Steven M. Wales, Daniel R. Knight, Thomas V. Riley, Dena Lyras, Paul A. Keller, Stephen G. Pyne

Research output: Contribution to journalArticle

Abstract

Clostridioides (formerly Clostridium) difficile is a Gram-positive anaerobic bacterial pathogen that causes severe gastrointestinal infection in humans. The current chemotherapeutic options are vastly inadequate, expensive and limited; this results in an exorbitant medical and financial burden. New, inexpensive chemotherapeutic treatments for C difficile infection with improved efficacy are urgently needed. A streamlined synthetic pathway was developed to allow access to 38 novel mono- and di-cationic biaryl 1,2,3-triazolyl peptidomimetics with increased synthetic efficiency, aqueous solubility and enhanced antibacterial efficacy. The monocationic arginine derivative 28 was identified as a potent, Gram-positive selective antibacterial with MIC values of 4 mu g/mL against methicillin-resistant Staphylococcus aureus and 8 g/mL against C difficile. Furthermore, the dicationic bis-triazole analogue 50 was found to exhibit broad-spectrum activity with substantial Gram-negative efficacy against Acinetobacter baumannii (8 mu g/mL), Pseudomonas aeruginosa (8 ugimL) and Klebsiella pneumoniae (16 ugimL); additionally, compound 50 displayed reduced haemolytic activity (

Original languageEnglish
Pages (from-to)203-224
Number of pages22
JournalEuropean Journal of Medicinal Chemistry
Volume170
DOIs
Publication statusPublished - 15 May 2019

Cite this

Tague, Andrew J. ; Putsathit, Papanin ; Hutton, Melanie L. ; Hammer, Katherine A. ; Wales, Steven M. ; Knight, Daniel R. ; Riley, Thomas V. ; Lyras, Dena ; Keller, Paul A. ; Pyne, Stephen G. / Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles targeting Clostridioides (Clostridium) difficile : Synthesis, antibacterial evaluation and an in vivo C. difficile infection model. In: European Journal of Medicinal Chemistry. 2019 ; Vol. 170. pp. 203-224.
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abstract = "Clostridioides (formerly Clostridium) difficile is a Gram-positive anaerobic bacterial pathogen that causes severe gastrointestinal infection in humans. The current chemotherapeutic options are vastly inadequate, expensive and limited; this results in an exorbitant medical and financial burden. New, inexpensive chemotherapeutic treatments for C difficile infection with improved efficacy are urgently needed. A streamlined synthetic pathway was developed to allow access to 38 novel mono- and di-cationic biaryl 1,2,3-triazolyl peptidomimetics with increased synthetic efficiency, aqueous solubility and enhanced antibacterial efficacy. The monocationic arginine derivative 28 was identified as a potent, Gram-positive selective antibacterial with MIC values of 4 mu g/mL against methicillin-resistant Staphylococcus aureus and 8 g/mL against C difficile. Furthermore, the dicationic bis-triazole analogue 50 was found to exhibit broad-spectrum activity with substantial Gram-negative efficacy against Acinetobacter baumannii (8 mu g/mL), Pseudomonas aeruginosa (8 ugimL) and Klebsiella pneumoniae (16 ugimL); additionally, compound 50 displayed reduced haemolytic activity (",
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Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles targeting Clostridioides (Clostridium) difficile : Synthesis, antibacterial evaluation and an in vivo C. difficile infection model. / Tague, Andrew J.; Putsathit, Papanin; Hutton, Melanie L.; Hammer, Katherine A.; Wales, Steven M.; Knight, Daniel R.; Riley, Thomas V.; Lyras, Dena; Keller, Paul A.; Pyne, Stephen G.

In: European Journal of Medicinal Chemistry, Vol. 170, 15.05.2019, p. 203-224.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles targeting Clostridioides (Clostridium) difficile

T2 - Synthesis, antibacterial evaluation and an in vivo C. difficile infection model

AU - Tague, Andrew J.

AU - Putsathit, Papanin

AU - Hutton, Melanie L.

AU - Hammer, Katherine A.

AU - Wales, Steven M.

AU - Knight, Daniel R.

AU - Riley, Thomas V.

AU - Lyras, Dena

AU - Keller, Paul A.

AU - Pyne, Stephen G.

PY - 2019/5/15

Y1 - 2019/5/15

N2 - Clostridioides (formerly Clostridium) difficile is a Gram-positive anaerobic bacterial pathogen that causes severe gastrointestinal infection in humans. The current chemotherapeutic options are vastly inadequate, expensive and limited; this results in an exorbitant medical and financial burden. New, inexpensive chemotherapeutic treatments for C difficile infection with improved efficacy are urgently needed. A streamlined synthetic pathway was developed to allow access to 38 novel mono- and di-cationic biaryl 1,2,3-triazolyl peptidomimetics with increased synthetic efficiency, aqueous solubility and enhanced antibacterial efficacy. The monocationic arginine derivative 28 was identified as a potent, Gram-positive selective antibacterial with MIC values of 4 mu g/mL against methicillin-resistant Staphylococcus aureus and 8 g/mL against C difficile. Furthermore, the dicationic bis-triazole analogue 50 was found to exhibit broad-spectrum activity with substantial Gram-negative efficacy against Acinetobacter baumannii (8 mu g/mL), Pseudomonas aeruginosa (8 ugimL) and Klebsiella pneumoniae (16 ugimL); additionally, compound 50 displayed reduced haemolytic activity (

AB - Clostridioides (formerly Clostridium) difficile is a Gram-positive anaerobic bacterial pathogen that causes severe gastrointestinal infection in humans. The current chemotherapeutic options are vastly inadequate, expensive and limited; this results in an exorbitant medical and financial burden. New, inexpensive chemotherapeutic treatments for C difficile infection with improved efficacy are urgently needed. A streamlined synthetic pathway was developed to allow access to 38 novel mono- and di-cationic biaryl 1,2,3-triazolyl peptidomimetics with increased synthetic efficiency, aqueous solubility and enhanced antibacterial efficacy. The monocationic arginine derivative 28 was identified as a potent, Gram-positive selective antibacterial with MIC values of 4 mu g/mL against methicillin-resistant Staphylococcus aureus and 8 g/mL against C difficile. Furthermore, the dicationic bis-triazole analogue 50 was found to exhibit broad-spectrum activity with substantial Gram-negative efficacy against Acinetobacter baumannii (8 mu g/mL), Pseudomonas aeruginosa (8 ugimL) and Klebsiella pneumoniae (16 ugimL); additionally, compound 50 displayed reduced haemolytic activity (

KW - Antibacterial

KW - Clostridioides (Clostridium) difficile

KW - Peptidomimetic

KW - Biaryl cationic amphiphiles

KW - Triazole

KW - LFF571

KW - FIDAXOMICIN

KW - DERIVATIVES

KW - VANCOMYCIN

KW - DISCOVERY

KW - EFFICACY

KW - SPECTRUM

KW - MIMICS

KW - AGENT

U2 - 10.1016/j.ejmech.2019.02.068

DO - 10.1016/j.ejmech.2019.02.068

M3 - Article

VL - 170

SP - 203

EP - 224

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -