Interrogating the nisin:lipid II interaction: a chemical biology approach

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Antibiotic resistant bacterial infections are becoming an increasing threat to global public health. A recently published UK Government document, the O'Neill report (2016) estimates that 10 million lives a year could be lost by 2050 if we do not tackle this issue. Part of the problem is that little investment in new antimicrobials has taken place in industry in decades, with the last new class of antibiotics discovered over 30 years ago. This has generated a renewed interest in natural products as a source of potent antimicrobial drugs. One class of natural products that are being intensively studied as possible leads are the lantibiotics. The best known of these, nisin, is produced by one strain of bacteria in order to kill off competing bacteria, and has been successfully used as a food preservative for many years. However, its complex structure, difficulties in synthesis, and poor biological properties mean that is has not yet been exploited as a possible antimicrobial drug to combat bacterial infections in humans. It is known that nisin targets a complex lipid, lipid II, which is only found in bacteria. As lipid II is critical for bacteria to be able to synthesise their cell wall, it is difficult for bacteria to evolve resistance to antimicrobial agents that target lipid II. Importantly, nisin and lipid II fit together to form an ordered pore structure that results in rupture of the bacterial membrane and the death of the bacterial cell. It is therefore very important that we understand how this pore forms and what the important interactions are between the nisin and lipid II components: however, current techniques for studying the structure of pores in membranes do not have high enough resolution to see the details of these interactions.The collaborating research groups have previously developed powerful methods for synthesising the challenging structures of nisin and lipid II, for analyzing how pore form in lipid membranes, and for screening new antibacterials against pathogens such as MRSA. In this proposal, we will systematically design and synthesise variants of nisin and lipid II, and for each structural variation we will then try to assemble the pore complex. The process will be akin to piecing together a 3-D jigsaw at the nanoscale, varying each of the pieces of the jigsaw one by one, to see which parts of the nisin and lipid II are crucial to successful assembly, and which parts are not involved in complex formation. This information will lead to a detailed model for the nisin:lipid II pore structure, and will eventually enable pharmaceutical companies to design simplified lantibiotics as leads for next generation antimicrobials.