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

Abstract

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.

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

“…This chemical group, common to all OP CWAs, plays a significant role in both molecular surface coordination properties and reactivity. Herein, we extend our prior work, which showed that simple, low level computational modelling may be used to predict hydrogen bond mediated aggregation events 26,27 and antimicrobial activity, 28 to identify appropriate OP CWA simulants for the development of supramolecular detection technologies, complementing the recent advances made in this area for hydrolysis siumulants. 25 Here, we hypothesised that neutral hydrogen bond donating receptors 1-4 ( Fig.…”

“…The energetics of association do not depend solely on a single molecular property, and we have previously shown that the use of an exhaustive, high throughput parameter search allows the rapid identification of predictive models. 28 To enable the elucidation of further association constant predictive models using Table 3 List of parameters (P) used to produce association constant predictive models and computational method used to derive each parameter. A definition for each of these parameters can be found within the ESI (Table S46 † N/A = non-applicable.…”

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

“…1). [14][15][16][17][18][19][20][21] Similar constructs developed by Faustino and co-workers have previously been shown to act as amphiphiles with enhanced surfactant properties, attributed to intermolecular hydrogen bonded self-association. 22,23 Additionally, Supuran et al have shown the promise of agents such as SSAs for development as therapeutics against Mycobacterium tuberculosis (TB).…”

“…16 Additionally, SSAs have also demonstrated antimicrobial activity against Gram-positive MRSA and Gram-negative E. coli. [14][15][16]20 This previous work has led us to hypothesise that SSA antimicrobial activity is linked to both molecular self-association and selective SSA:phospholipid complexation, resulting in molecular membrane permeation events. 15,16,25,26 Additionally, not only have we shown SSAs to arrive at the external microbial membrane as self-associated spherical aggregates, 16 but that these aggregates can incorporate small drug(like) guest species.…”

“…[14][15][16]20 This previous work has led us to hypothesise that SSA antimicrobial activity is linked to both molecular self-association and selective SSA:phospholipid complexation, resulting in molecular membrane permeation events. 15,16,25,26 Additionally, not only have we shown SSAs to arrive at the external microbial membrane as self-associated spherical aggregates, 16 but that these aggregates can incorporate small drug(like) guest species. 17 The summation of this evidence has therefore led us to hypothesise that this class of compound has the potential to act as efficacy enhancers for other therapeutic agents.…”