Multidisciplinary toolbox for characterising lipid II binding antibiotics
Lead Research Organisation:
University of Warwick
Department Name: Chemistry
Abstract
Antimicrobial resistance is a growing global problem with wide ranging societal and economic implications. Whilst the focus is often on the impact on human medicine, it is also a concern for food security (including food spoilage) and animal health and welfare.
Antibiotics targeting lipid II, which is the basic substrate in the biosynthesis of the bacterial cell wall, are excellent drug candidates. It is far more difficult to develop resistance when substrates are targeted rather than, e.g., proteins. However, lipid II binding molecules often also have physico-chemical properties that make them challenging to apply, e.g., in clinic. If molecular level understanding on how they work is available, molecules preserving the binding properties of the original antibiotics but also exhibiting more favorable properties for applications can be engineered.
This project will focus on developing a streamlined toolbox composed of reagents, biophysical/structural measurement methods and molecular dynamics simulations to characterise interactions of antibiotics and lipid II at atomic resolution to facilitate their engineering. In order to make the approach generally applicable to any lipid II binder, we will focus on developing methodology that uses lipid II itself as a reporter on the interactions.
The work described will be able to make use of collaborations across the physical and life sciences utilizing a capability to synthesise high purity isotopically labelled lipid II and complementary nature of solution and solid-state nuclear magnetic resonance (NMR) and computational methods. The experiments can be carried out in a range of membrane compositions to determine how the environment affects the antibiotic-lipid II complex and to determine its suitability for high resolution structure determination. Our approach will be a highly valuable pathway for characterisation, validation, and refinement of new lipid II binding antibiotics. We will validate it on a set of antibiotics with known modes of action and test it on a recently discovered antibiotic for which binding to lipid II is not known.
Antibiotics targeting lipid II, which is the basic substrate in the biosynthesis of the bacterial cell wall, are excellent drug candidates. It is far more difficult to develop resistance when substrates are targeted rather than, e.g., proteins. However, lipid II binding molecules often also have physico-chemical properties that make them challenging to apply, e.g., in clinic. If molecular level understanding on how they work is available, molecules preserving the binding properties of the original antibiotics but also exhibiting more favorable properties for applications can be engineered.
This project will focus on developing a streamlined toolbox composed of reagents, biophysical/structural measurement methods and molecular dynamics simulations to characterise interactions of antibiotics and lipid II at atomic resolution to facilitate their engineering. In order to make the approach generally applicable to any lipid II binder, we will focus on developing methodology that uses lipid II itself as a reporter on the interactions.
The work described will be able to make use of collaborations across the physical and life sciences utilizing a capability to synthesise high purity isotopically labelled lipid II and complementary nature of solution and solid-state nuclear magnetic resonance (NMR) and computational methods. The experiments can be carried out in a range of membrane compositions to determine how the environment affects the antibiotic-lipid II complex and to determine its suitability for high resolution structure determination. Our approach will be a highly valuable pathway for characterisation, validation, and refinement of new lipid II binding antibiotics. We will validate it on a set of antibiotics with known modes of action and test it on a recently discovered antibiotic for which binding to lipid II is not known.
