An optimised Cu(0)-RDRP approach for the synthesis of lipidated oligomeric vinyl azlactone: toward a versatile antimicrobial materials screening platform

Grace, James L.; Amado, Maite; Reid, Janet C.; Elliott, Alysha G.; Landersdorfer, Cornelia B.; Truong, Nghia P.; Kempe, Kristian; Cooper, Matthew A.; Davis, Thomas P.; Montembault, Véronique; Pascual, Sagrario; Fontaine, Laurent; Velkov, Tony; Quinn, John F.; Whittaker, Michael R.

doi:10.1039/c9tb01624d

Cited by 15 publications

(18 citation statements)

References 61 publications

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“…Similar to cytotoxicity assays previously described, − human HEK293 cells (20 μL) were seeded at 5000 cells per well in 384-well plates. Cells were cultured in DMEM, supplemented with 10% fetal bovine serum, and 50 U/mL penicillin, and 50 mg/mL streptomycin, for 24 h at 37 °C, 5% CO 2 .…”

Section: General Experimental Sectionmentioning

confidence: 99%

Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones with Improved Potency and Solubility

et al. 2020

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Following the approval of delamanid and pretomanid as new drugs to treat drug-resistant tuberculosis, there is now a renewed interest in bicyclic nitroimidazole scaffolds as a source of therapeutics against infectious diseases. We recently described a nitroimidazopyrazinone bicyclic subclass with promising antitubercular and antiparasitic activity, prompting additional efforts to generate analogs with improved solubility and enhanced potency. The key pendant aryl substituent was modified by (i) introducing polar functionality to the methylene linker, (ii) replacing the terminal phenyl group with less lipophilic heterocycles, or (iii) generating extended biaryl side chains. Improved antitubercular and antitrypanosomal activity was observed with the biaryl side chains, with most analogs achieved 2- to 175-fold higher activity than the monoaryl parent compounds, with encouraging improvements in solubility when pyridyl groups were incorporated. This study has contributed to understanding the existing structure–activity relationship (SAR) of the nitroimidazopyrazinone scaffold against a panel of disease-causing organisms to support future lead optimization.

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Section: General Experimental Sectionmentioning

confidence: 99%

Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones with Improved Potency and Solubility

et al. 2020

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“…The effects of SrtAI-loaded and non-loaded MSNs, AMPs (PEX, INDO, and MASTO), and their combinations on HEK-293 cell viability were evaluated using a resazurin-based assay [ 37 ] to determine if their synergistic combinations could reduce toxicity associated with individual components and if the phosphonate modification of MCM-41 MSNs affects toxicity. Concentrations ( Table S1 ) based on a two-fold dilution series, which ensure two concentrations below and three concentrations above the MIC ( Table 3 ) or synergistic concentrations determined by ΣFIC ( Table 4 ) against MSSA, were used.…”

Section: Resultsmentioning

confidence: 99%

Formulation and Biological Evaluation of Mesoporous Silica Nanoparticles Loaded with Combinations of Sortase A Inhibitors and Antimicrobial Peptides

et al. 2022

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This study aimed to develop synergistic therapies to treat superbug infections through the encapsulation of sortase A inhibitors (SrtAIs; trans-chalcone (TC), curcumin (CUR), quercetin (QC), or berberine chloride (BR)) into MCM-41 mesoporous silica nanoparticles (MSNs) or a phosphonate-modified analogue (MCM-41-PO3−) to overcome their poor aqueous solubility. A resazurin-modified minimum inhibitory concentration (MIC) and checkerboard assays, to measure SrtAI synergy in combination with leading antimicrobial peptides (AMPs; pexiganan (PEX), indolicidin (INDO), and [I5, R8] mastoparan (MASTO)), were determined against methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. The results demonstrated that the MCM-41 and MCM-41-PO3− formulations significantly improved the aqueous solubility of each SrtAI. The MICs for SrtAI/MCM-41-PO3− formulations were lower compared to the SrtAI/MCM-41 formulations against tested bacterial strains, except for the cases of BR/MCM-41 and QC/MCM-41 against P. aeruginosa. Furthermore, the following combinations demonstrated synergy: PEX with TC/MCM-41 (against all strains) or TC/MCM-41-PO3− (against all strains except P. aeruginosa); PEX with BR/MCM-41 or BR/MCM-41-PO3− (against MSSA and MRSA); INDO with QC/MCM-41 or QC/MCM-41-PO3− (against MRSA); and MASTO with CUR/MCM-41 (against E. coli). These combinations also reduced each components’ toxicity against human embryonic kidney cells. In conclusion, MCM-41 MSNs provide a platform to enhance SrtAI solubility and demonstrated antimicrobial synergy with AMPs and reduced toxicity, providing novel superbug treatment opportunities.

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“…Therefore, the controllability of the polymerization process is very important. Efficient and controllable polymerization methods such as reversible addition–fragmentation chain transfer (RAFT) polymerization, atom transfer radical polymerization (ATRP), reversible-deactivation radical polymerization (RDRP), and ring-opening metathesis polymerization (ROMP) are usually chosen to precisely control the composition of hydrophilic and hydrophobic segments. For example, Hartlieb et al developed a polymeric antimicrobial peptide mimic featuring a bottlebrush architecture by RAFT and ROMP .…”

Section: Introductionmentioning

confidence: 99%

Screening and Matching Amphiphilic Cationic Polymers for Efficient Antibiosis

et al. 2020

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The amphiphilic cationic polymers that mimic antimicrobial peptides have received increasing attention due to their excellent antibacterial activity. However, the relationship between the structure of cationic polymers and its antibacterial effect remains unclear. In our current work, a series of PEG blocked amphiphilic cationic polymers composed of hydrophobic alkyl-modified and quaternary ammonium salt (QAS) moieties have been prepared. The structure–antibacterial activity relationship of these cationic polymers was investigated against E. coli and S. aureus, including PEGylation, random structure, molecular weights, and the content and lengths of the hydrophobic alkyl side chains. The results indicated that PEGylated random amphiphilic cationic copolymer (mPB35/T57) showed stronger antibacterial activity and better biocompatibility than the random copolymer without PEG (PB33/T56). Furthermore, mPB35/T57 with appropriate mole fraction of alkyl side chains (f alkyl = 0.38), degree of polymerization (DP = 92), and four-carbon hydrophobic alkyl moieties was found to have the optimal structure that revealed the best antibacterial activities against both E. coli (MIC = 8 μg/mL, selectivity > 250) and S. aureus (MIC = 4 μg/mL, selectivity > 500). More importantly, mPB35/T57 could effectively eradicate E. coli biofilms by killing the bacteria embedded in the biofilms. Therefore, the structure of mPB35/T57 provided valuable information for improving the antibacterial activity of cationic polymers.

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An optimised Cu(0)-RDRP approach for the synthesis of lipidated oligomeric vinyl azlactone: toward a versatile antimicrobial materials screening platform

Abstract: For the first time Cu(0)-RDRP conditions were optimised to allow for the fast and controlled polymerisation of vinyl azlactone with tuneable lipid elements: a versatile platform material for the high-throughput synthesis of antimicrobial materials.

Cited by 15 publications

References 61 publications

Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones with Improved Potency and Solubility

Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones with Improved Potency and Solubility

Formulation and Biological Evaluation of Mesoporous Silica Nanoparticles Loaded with Combinations of Sortase A Inhibitors and Antimicrobial Peptides

Screening and Matching Amphiphilic Cationic Polymers for Efficient Antibiosis

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