Bisbiguanide analogues as probes for assessing membrane barrier function in multidrug resistant Gram-negative bacteria.

Aim:
The key aim of this project is to develop a number of bisbiguanide-based membrane active probes to investigate the barrier properties of the Gram-negative membrane. The overarching aim is to identify chemical features of small molecules that enable them to penetrate and accumulate inside Gram-negative bacteria.
Remit:
This project aligns with the BBSRC "Bioscience for Health" theme and addresses BBSRC priority "Combatting Antimicrobial Resistance" (specifically "underpinning the development of novel antimicrobials and alternatives to antimicrobials"). This project focuses on mechanistic understanding of "effects and interactions of drugs with cells", "understanding the mechanisms of drug resistance, prevention and combating drug resistance" and inlcludes "research that underpins the development of strategies to mitigate the effects of antimicrobial resistance", "technology development for replacing animal use in drug testing". As such the project is well aligned with BBSRC remit.
Background, Rational and Importance:
The discovery of new antibiotics effective against Gram-negative bacteria is a major challenge due to the permeability barrier of two-membrane cell envelope of Gram-negative bacteria and limited chemical diversity of compound libraries to probe this barrier. The expansion of the chemical space of antibacterial tool compounds and identification of compounds that can penetrate the Gram-negative membrane barrier is urgent to understand the chemical features of compounds that are able to overcome the Gram-negative membrane barrier. The industrial applicants have previously been involved in screening of the Prestwick Chemical Library, commissioned by ANTRUK, and identified a small limited number of compounds which either showed direct antimicrobial effects against MDR Gram-negative pathogens or which were able to synergise with specific antibiotics to potentiate their activity against...