Molecular interactions between bacterial membrane lipids and Gemini surfactants

Abstract

Cationic surfactants have seen widespread use as disinfectants for decades in various fields, such as the food industry and in hospitals. Unlike traditional antibiotics which target specific sites on enzymes or membranes to disrupt cell functions, the amphiphilic nature of cationic surfactants causes them to embed into bacterial membranes via hydrophobic interactions, a non-specific mechanism that is thought to be more difficult to mutate against. The first resistant gene to these molecules, qacA, was discovered in 1985, controlling the production of membrane affiliated efflux pumps that are specific to mono- and bis-cationic substrates. The gemini surfactant octenidine dihydrochloride (OCT) is a clinical antiseptic, in use for more than 40 years, with no resistant mutations observed until 2021. Despite this, little is known about the specific molecular interactions that underpin the remarkable efficacy of its antimicrobial mechanism. It is thought that through charge, H-bonding and π-system interactions, the 4-aminopyridinium headgroup of OCT is essential to the antimicrobial efficacy, and so further mechanistic understanding of how it disrupts membranes will allow for better design of variants that evade resistance. Scattering techniques, specifically small/wide angle X-ray scattering (SAXS/WAXS), small-angle neutron scattering (SANS) and neutron reflectivity (NR), provide a non-invasive means of monitoring the membrane bilayer structure as OCT and variants such as quaternary ammonium geminis (alkyl 8-10-8) are added to challenge the membrane. Ternary liposomes comprising DPPE, DPPG and cardiolipin have been prepared to mimic the cytoplasmic membrane of E. coli, with LPS-smooth self-assemblies and monolayers used to investigate interactions with the E. coli outer membrane. These measurements, combined witha range of other complementary techniques, revealed similar interactions between ammonium or 4-aminopyridinium headgroups and ternary liposomes, but unveiled that 4-aminopyridinium interacts differently with LPS-smooth.

Date of Award	18 Mar 2025
Original language	English
Awarding Institution	University of Bristol
Supervisor	Wuge H Briscoe (Supervisor), Julian Eastoe (Supervisor), Eric Robles (Supervisor), Eva Perez-Prat (Supervisor) & Rebecca Fong (Supervisor)