Establishing the selective phospholipid membrane coordination, permeation and lysis properties for a series of ‘druggable’ supramolecular self-associating antimicrobial amphiphiles

Abstract

A combination of computational and synthetic phospholipid vesicle/nanodisc assays are used to investigate the mode of action for a class of antimicrobial agents, while a range of DMPK studies establish agent druggability.

A water-soluble membrane transporter for biologically relevant cations

“…However, we suggest that these concentration dependent mass ion transport events could be representative of SSA 1 operating through a mechanism analogous to the antimicrobial peptide “carpet model” in the presence of anionophore 4 . 21,31,32 Here, peptides accumulate on the bilayer surface until they reach a critical concentration at which membrane disruption can occur. 32…”

“…Despite their modest efficacy, this retention of transport activity using 100% H 2 O as the delivery vehicle represents a step-change in the development of deliverable ionophores, particularly given the established pharmacological profile of this molecule. 21 …”

“…19,20 In addition, SSA 1 has recently been subjected to pre-clinical trials in mice and was found to exhibit a druggable profile, demonstrating target tissue distribution (lung/muscle/liver) and excretion via the bloodstream. 21…”

Controlling the structure of supramolecular fibre formation for benzothiazole based hydrogels with antimicrobial activity against methicillin resistantStaphylococcus aureus

“…The hypothesised mode of action for these SSAs include selective membrane coordination and disruption. 23 Furthermore, SSAs have been shown to: (i) act as (potential) drug delivery systems; 24,25 (ii) enhance the activity of commonly used antimicrobials including; novobiocin and rifampicin against a variety of bacteria such as the ESKAPE pathogen, Pseudomonas aeruginosa; 26,27 (iii) enhance the activity of cisplatin against ovarian cancer cells; 28 and (iv) exhibit a druggable profile when administered intravenously to mice. 23 In general, the anionic portion of an SSA is known to selfassociate, through the formation of (thio)urea-anion intermolecular hydrogen bonds, to form anionic dimers in the solid state (Fig.…”

Noncovalent Bile Acid Oligomers as Facial Amphiphilic Antimicrobials

“…Antimicrobial peptides and antifungal peptides (both denoted AMP) , are considered a new weapon against antibiotic-resistant microorganisms. − AMPs usually form helical or layered structures with separate hydrophilic and hydrophobic faces, which is also referred to as facial amphiphilicity. This specific amphiphilic structure allows most of the AMPs to electrostatically bind to the negatively charged bacterial membrane and leads to cell death. − Moreover, the physical destruction of the cell membrane makes it difficult for microorganisms to produce drug resistance. − Therefore, a lot of effort has been put forward to develop AMP-based fungicides that have shown very promising applications. − …”