Bacteria that resist antibiotics are becoming harder to treat, and one promising target for new drugs is a molecule called lipid II—an essential building block for bacterial cell walls. This project addresses a specific bottleneck: many antibiotics that bind to lipid II are chemically difficult to use in practice, for example because they are unstable or hard to deliver in the body. Without a detailed understanding of how these molecules interact at the atomic level, it is difficult to engineer better versions. The researchers aim to build a toolkit—combining labelled lipid II, nuclear magnetic resonance (NMR) spectroscopy, and computer simulations—that can reveal exactly how any antibiotic binds to lipid II, in different membrane environments. If successful, the approach could accelerate the development of new antibiotics that are both effective against resistant bacteria and more practical to manufacture and administer. This matters not only for human medicine but also for food security, since resistant bacteria spoil crops and threaten animal health. The work is fundamental science: it does not deliver a drug directly, but it provides the molecular-level insight needed to rationally design one. Similar fundamental studies of bacterial cell wall synthesis have previously underpinned entire classes of antibiotics.
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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.
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