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, P. A.; Pyne, Stephen G.

doi:10.1016/j.ejmech.2019.02.068

Cited by 17 publications

(14 citation statements)

References 46 publications

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“…However, they were generally less active against the other Gram-positive and Gram-negative bacteria ( Table 1 ). The relative solubility ratios (relative to compound 1 ) [ 13 ] for 40 and 42 were 5 and 4 with CLogP values of 4.46 and 4.39, respectively, when compared to 1 with a ClogP of 7.47. Therefore, despite the better solubility profiles of these compounds, they failed to show better activity against C. difficile .…”

Section: Resultsmentioning

confidence: 99%

“…Hemolysis assay (human erythrocytes) –HC 50 determination. These were performed as described previously [ 13 , 29 ].…”

Section: Methodsmentioning

confidence: 99%

“…There are many potential chemotherapeutics undergoing clinical trials for the treatment of CDI [ 12 ]. Other small molecule chemotherapeutics currently under investigation for use against C. difficile , include antimicrobial peptidomimetics [ 13 , 14 , 15 ], glycopeptides [ 16 ], bis-indoles [ 17 ], purine derivatives [ 18 ], tetramic acids [ 19 ], nitroheterocycles [ 20 ], macrolides [ 21 ], and nylon-3 polymers [ 22 ]. Two vaccines are being investigated in clinical trials (Pfizer and Intercell [ 23 ]), whereas bezlotoxumab (a monoclonal antibody targeting C. difficile TcdB) was given FDA approval in 2016 as adjunctive therapy for patients undergoing antimicrobial treatment who were at high risk of recurrent infection [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

“…This led to the identification of compound 1 with potent antibacterial activity against drug resistant Gram-positive bacteria with potential for topical applications ( Figure 1 ) [ 25 ]. More recent work in our laboratory has identified compounds 2 – 4 from a class of small molecule cationic amphiphilic 1,1′-biarylpeptidomimetics that exert antibacterial activity through cytoplasmic membrane disruption [ 13 , 14 ]. These compounds have IC 50 values of 4–8 μg/mL against C. difficile ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

“…Unfortunately compound 3 showed poor solubility with precipitation during preparation in a 10% DMSO solution, and high in vitro hemolytic activity against HEK293 cells. While compound 4 showed promising in vitro properties, it performed poorly in the C. difficile murine model with a survival rate of 60% after 24 h, but a 0% rate after 48 h [ 13 ], despite its low hemolytic activity. Despite some positive results, more water-soluble derivatives with lower hemolytic activity for further in vivo murine CDI model studies needed to be developed.…”

Section: Introductionmentioning

confidence: 99%

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Cationic Peptidomimetic Amphiphiles Having a N-Aryl- or N-Naphthyl-1,2,3-Triazole Core Structure Targeting Clostridioides (Clostridium) difficile: Synthesis, Antibacterial Evaluation, and an In Vivo C. difficile Infection Model

et al. 2021

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Clostridioides (also known as Clostridium) difficile is a Gram-positive anaerobic, spore producing bacterial pathogen that causes severe gastrointestinal infection in humans. The current chemotherapeutic options are inadequate, expensive, and limited, and thus inexpensive drug treatments for C. difficile infection (CDI) with improved efficacy and specificity are urgently needed. To improve the solubility of our cationic amphiphilic 1,1′-binaphthylpeptidomimetics developed earlier that showed promise in an in vivo murine CDI model we have synthesized related compounds with an N-arytriazole or N-naphthyltriazole moiety instead of the 1,1′-biphenyl or 1,1′-binaphthyl moiety. This modification was made to increase the polarity and thus water solubility of the overall peptidomimetics, while maintaining the aromatic character. The dicationic N-naphthyltriazole derivative 40 was identified as a C. difficile-selective antibacterial with MIC values of 8 µg/mL against C. difficile strains ATCC 700057 and 132 (both ribotype 027). This compound displayed increased water solubility and reduced hemolytic activity (32 µg/mL) in an in vitro hemolysis assay and reduced cytotoxicity (CC50 32 µg/mL against HEK293 cells) relative to lead compound 2. Compound 40 exhibited mild efficacy (with 80% survival observed after 24 h compared to the DMSO control of 40%) in an in vivo murine model of C. difficile infection by reducing the severity and slowing the onset of disease.

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Section: Resultsmentioning

confidence: 99%

“…Hemolysis assay (human erythrocytes) –HC 50 determination. These were performed as described previously [ 13 , 29 ].…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Cationic Peptidomimetic Amphiphiles Having a N-Aryl- or N-Naphthyl-1,2,3-Triazole Core Structure Targeting Clostridioides (Clostridium) difficile: Synthesis, Antibacterial Evaluation, and an In Vivo C. difficile Infection Model

et al. 2021

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Visible Light Induced Aerobic Coupling of Arylboronic Acids Promoted by Hydrazone

et al. 2022

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A visible-light-induced oxidative coupling of arylboronic acids has been developed for the synthesis of biaryls. The reaction that employs polydentate hydrazones as the bifunctional catalyst works smoothly under room temperature. It is compatible with a wide range of functional group. The study of UV-Vis spectrum indicated that hydrazone and its complex with CuI show major absorptions upon visible-light, which secures the dual role of hydrazone as both ligand and photocatalyst in this reaction. Hence, the reaction is proposed to involve stepwise transmetallations, photo-induced oxidations, and reductive elimination.

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Single Molecule Non-cleavable Multiply Active Antibacterials

Bremner

2021

Multiple Action-Based Design Approaches to Antibacterials

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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

Cited by 17 publications

References 46 publications

Cationic Peptidomimetic Amphiphiles Having a N-Aryl- or N-Naphthyl-1,2,3-Triazole Core Structure Targeting Clostridioides (Clostridium) difficile: Synthesis, Antibacterial Evaluation, and an In Vivo C. difficile Infection Model

Cationic Peptidomimetic Amphiphiles Having a N-Aryl- or N-Naphthyl-1,2,3-Triazole Core Structure Targeting Clostridioides (Clostridium) difficile: Synthesis, Antibacterial Evaluation, and an In Vivo C. difficile Infection Model

Visible Light Induced Aerobic Coupling of Arylboronic Acids Promoted by Hydrazone

Single Molecule Non-cleavable Multiply Active Antibacterials

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