Towards the use of (pseudo) nucleobase substituted amphiphiles as DNA nucleotide mimics and antimicrobial agents

Ng, Kendrick K. L.; Dimitrovski, Milan; Boles, Jessica E.; Ellaby, Rebecca J.; White, Lisa J.; Hiscock, Jennifer R.

doi:10.1080/10610278.2020.1755038

Cited by 5 publications

(9 citation statements)

References 40 publications

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“…When comparing the fit of 1 H NMR dilution data for SSAs 1 – 4 to both the EK and CoEK binding isotherms, lower fitting errors were observed consistently for the (dimerization)EK over the CoEK model. This is consistent with previous observations made for >30 SSAs studied to date [ 18 , 20 , 22 ].…”

Section: Resultssupporting

confidence: 93%

“…Previously published high resolution electrospray ionisation (ESI) mass spectrometry studies have shown the anionic portion of most SSAs to exist as dimeric species [ 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. Data previously obtained for SSAs 1 [ 16 ], 2 [ 21 ] and 4 [ 18 ] confirmed the presence of SSA anionic dimers under these experimental conditions.…”

Section: Resultsmentioning

confidence: 99%

“…Table 3 shows the results of data analysis performed for solutions 1 – 11 and co-formulations a – j in: (i) DMSO- d 6 , standardised with 1.0% DCM and (ii) D 2 O standardised with 5.0% ethanol. The majority of SSA studies conducted to date show that in DMSO- d 6 based solutions many of those self-associated structures formed are anionic dimers, at concentrations up to 112 mM [ 18 , 20 , 22 ]. This trend was also observed for the majority of SSAs and co-formulations discussed herein under the same experimental conditions.…”

Section: Resultsmentioning

confidence: 99%

“…To date, a library of >50 SSAs and structurally related compounds have been synthesized. The self-associative properties of this compound library and any resultant aggregate structure have also been characterised, using a variety of complementary experimental techniques ( Figure 1 ) [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. A series of solid state, single crystal X-ray diffraction studies have shown the intermolecular binding mode adopted by the anionic component of an SSA to be cation dependent [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, examples from this SSA library have been shown to act as antimicrobial agents against both clinically relevant model Gram-positive (methicillin resistant Staphylococcus aureus —MRSA) and Gram-negative ( Escherichia coli ) bacteria [ 21 , 22 , 23 ]. Within the scope of our studies we have also hypothesised that SSA antimicrobial activity is related to both molecular self-association [ 23 ] and selective SSA:phospholipid complexation [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

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Towards the Application of Supramolecular Self-Associating Amphiphiles as Next-Generation Delivery Vehicles

et al. 2020

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Herein, we present a series of supramolecular self-associating amphiphilic (SSA) salts and establish the potential for these molecular constructs to act as next-generation solution-state molecular delivery vehicles. We characterise the self-association of these SSAs, both alone and when co-formulated with a variety of drug(like) competitive guest species. Single crystal X-ray diffraction studies enable the observation of hydrogen-bonded self-association events in the solid state, whilst high resolution mass spectrometry confirms the presence of anionic SSA dimers in the gas-phase. These same anionic SSA dimeric species are also identified within a competitive organic solvent environment (DMSO-d6/0.5% H2O). However, extended self-associated aggregates are observed to form under aqueous conditions (H2O/5.0% EtOH) in both the absence and presence of these competitive guest species. Finally, through the completion of these studies, we present a framework to support others in the characterisation of such systems.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Towards the Application of Supramolecular Self-Associating Amphiphiles as Next-Generation Delivery Vehicles

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Anionic Self‐Assembling Supramolecular Enhancers of Antimicrobial Efficacy against Gram‐Negative Bacteria

Boles

Williams

Allen

et al. 2022

Advanced Therapeutics

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As a result of the looming antimicrobial resistance crisis, there is an urgent need for novel antimicrobial treatments. This is particularly true for hard‐to‐treat Gram‐negative bacteria, as many antimicrobial agents are unable to cross the cell membrane to gain access to the cell interior, and thus elicit a therapeutic response. Herein, evidence is provided of the use of anionic supramolecular self‐associating amphiphiles (SSAs) as antimicrobial efficacy enhancers for commonly used antimicrobial agents, to which there is known resistance, against Gram‐negative bacteria. The co‐administration of the SSAs with antimicrobials is shown to sensitize traditionally hard to treat Pseudomonas aeruginosa to both rifampicin and novobiocin, from which structure activity relationships can be elucidated. Quantitative fluorescence microscopy is performed, indicating membrane permeabilization to be the likely mode of action of drug efficacy enhancement by the SSAs. These results offer an alternative strategy in antimicrobial adjuvant design, expanding focus beyond cationic peptides and into the realm of anionic small molecules. Finally, the self‐assembly of the SSAs in the presence of these antimicrobials is investigated through a combination of quantitative NMR, tensiometry, dynamic light scattering, and zeta potential studies, demonstrating the impact of these agents on SSA self‐association events.

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Towards the Prediction of Antimicrobial Efficacy for Hydrogen Bonded, Self‐Associating Amphiphiles

et al. 2020

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Herein we report 50 structurally related supramolecular selfassociating amphiphilic (SSA) salts and related compounds. These SSAs are shown to act as antimicrobial agents, active against model Gram-positive (methicillin-resistant Staphylococcus aureus) and/or Gram-negative (Escherichia coli) bacteria of clinical interest. Through a combination of solution-state, gasphase, solid-state and in silico measurements, we determine 14 different physicochemical parameters for each of these 50 structurally related compounds. These parameter sets are then used to identify molecular structure-physicochemical propertyantimicrobial activity relationships for our model Gram-negative and Gram-positive bacteria, while simultaneously providing insight towards the elucidation of SSA mode of antimicrobial action.

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Towards the use of (pseudo) nucleobase substituted amphiphiles as DNA nucleotide mimics and antimicrobial agents

Abstract: The version in the Kent Academic Repository may differ from the final published version. Users are advised to check http://kar.kent.ac.uk for the status of the paper. Users should always cite the published version of record.

Cited by 5 publications

References 40 publications

Towards the Application of Supramolecular Self-Associating Amphiphiles as Next-Generation Delivery Vehicles

Towards the Application of Supramolecular Self-Associating Amphiphiles as Next-Generation Delivery Vehicles

Anionic Self‐Assembling Supramolecular Enhancers of Antimicrobial Efficacy against Gram‐Negative Bacteria

Towards the Prediction of Antimicrobial Efficacy for Hydrogen Bonded, Self‐Associating Amphiphiles

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