Supramolecular Self-associating Amphiphiles (SSAs) as enhancers of antimicrobial agents towards Escherichia coli (E. coli)

Supramolecular self-associating amphiphiles (SSAs) are a class of amphiphilic salt which have demonstrated antimicrobial activity against both Gram-positive and Gram-negative bacteria. Herein, we show that SSAs are also able to increase the efficacy of a range of currently used antimicrobial/therapeutic agents with a range of different chemical structures and modes of antimicrobial action against Gram-negative Escherichia coli, which include: octenidine (an antiseptic); ampicillin (an antibiotic); and cisplatin (a DNA chelating agent). Additionally, we show these effects to be dependent on the order of agent addition. Finally, through completion of a range of 1[thin space (1/6-em)]:[thin space (1/6-em)]1 SSA[thin space (1/6-em)]:[thin space (1/6-em)] antimicrobial/therapeutic agent physicochemical studies we gain an understanding as to how the self-association events and resultant SSA aggregate structure are effected by the presence of these secondary molecular species

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

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

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

Here we present the synthesis of complementary (pseudo) nucleobase appended Supramolecular Self-associating Amphiphilic (SSA) salts and, establish the potential for this molecular construct to produce a new class of DNA inspired synthetic structures/materials. The anionic component of this class of amphiphile contains multiple hydrogen bond donating and accepting functionalities, meaning that these systems can access multiple self-associative hydrogen bonding modes simultaneously. Herein, we characterise the self-associative properties of these DNA inspired amphiphiles in the solid state, solution state and gas phase. Finally, we investigate the potential of these amphiphilic salts to act as antimicrobial agents against model Gram-positive (methicillin resistant Staphylococcus aureus – MRSA) and Gram-negative (Escherichia coli – E. coli) bacteria

Towards the prediction of antimicrobial efficacy for hydrogen bonded, self-associating amphiphiles

Herein, we report 50 structurally related supramolecular self-associating 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, gas phase, 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 property – antimicrobial activity relationships for our model Gram-negative and Gram-positive bacteria, while simultaneously providing insight towards the elucidation of SSA mode of antimicrobial action

A Symbiotic Supramolecular Approach to the Design of Novel Amphiphiles with Antibacterial Properties Against MSRA

Herein, we identify Supramolecular Self-associating Amphiphiles (SSAs) as a novel class of antibacterials with activity towards Methicillin-resistant Staphylococcus aureus. Structure-activity relationships have been identified in the solid, solution and gas phases. Finally, we show that when supplied in combination, SSAs exhibit increased antibacterial efficacy against these clinically relevant microbes

Identification of organophosphorus simulants for the development of next-generation detection technologies

Organophosphorus (OP) chemical warfare agents (CWAs) represent an ongoing threat but the understandable widespread prohibition of their use places limitations on the development of technologies to counter the effects of any OP CWA release. Herein, we describe new, accessible methods for the identification of appropriate molecular simulants to mimic the hydrogen bond accepting capacity of the P[double bond, length as m-dash]O moiety, common to every member of this class of CWAs. Using the predictive methodologies developed herein, we have identified OP CWA hydrogen bond acceptor simulants for soman and sarin. It is hoped that the effective use of these physical property specific simulants will aid future countermeasure developments

Di-anionic self-associating supramolecular amphiphiles (SSAs) as antimicrobial agents against MRSA and Escherichia coli

Herein, we report a series of di-anionic supramolecular self-associating amphiphiles (SSAs). We elucidate the antimicrobial properties of these SSAs against both methicillin resistant Staphylococcus aureus and Escherichia coli. In addition, we show this class of compound to form both intra- and intermolecular hydrogen bonded macrocyclic structures in the solid state

Predicting the antimicrobial efficacy of hydrogen bonded, self‐associating amphiphiles

Herein, we report 50 structurally related supramolecular self‐associating 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, gas phase, 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 property – antimicrobial activity relationships for our model Gram‐negative and Gram‐positive bacteria, while simultaneously providing insight towards the elucidation of SSA mode of antimicrobial action

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant