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 language | English |
|---|---|
| Pages (from-to) | 203-224 |
| Number of pages | 22 |
| Journal | European Journal of Medicinal Chemistry |
| Volume | 170 |
| DOIs | |
| Publication status | Published - 15 May 2019 |
Cite this
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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 journal › Article
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 -