Determining how polymyxins kill bacteria

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Bacteria cause many different infections, which can rapidly progress from mild to life-threatening. Ordinarily, a short course of antibiotics is sufficient to clear the infection. However, an increasing number of infections are caused by bacteria that can resist many different types of antibiotics. The World Health Organisation has determined that the most worrying types of resistant bacteria are all Gram-negative, which have an outer cell envelope that consists of two lipid membranes separated by a cell wall. These bacteria are resistant to many different classes of antibiotics, including those known as beta-lactams, which are the most commonly used antibiotics globally.One type of antibiotic that many bacteria are still susceptible to are the polymyxins, of which two are used clinically, polymyxin B and polymyxin E (more commonly known as colistin). Unfortunately, polymyxins don't work as well as other antibiotics and often damage the patient's kidneys. Furthermore, resistance to polymyxins is an ever-increasing problem. This is partly due to increased use of these drugs and also because a type of polymyxin resistance known as MCR can spread between bacteria.Polymyxins damage the outer membrane by targeting a chemical called LPS on the surface of bacteria. Work from our group revealed that polymyxins also damage the inner membrane by targeting LPS and that this damage is required to kill bacteria. However, the reasons why polymyxin targeting of LPS in the inner membrane causes damage is unclear and will be resolved in this proposal. Having determined how polymyxins kill bacteria, we will then investigate how polymyxin resistance protects bacteria from this class of antibiotics, as well as the costs associated with resistance.Finally, we have discovered that an experimental antibiotic called murepavadin can make bacteria very sensitive to killing by polymyxins, including strains that are polymyxin resistant. By understanding how this happens, we can devise strategies to reverse polymyxin resistance.Combined, this project will provide insight into how polymyxins kill bacteria, how polymyxin resistance functions and how polymyxin resistance can be reversed.