Development of antimicrobial peptides against Gram-negative antibiotic resistant pathogens

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The underuse and overuse of antibiotics has resulted in Gram-negative bacteria becoming resistant to known antibiotics. Although this is a global problem, the lack of new antibiotics and alternative therapy is of concern especially in SA, where patients with a weakened immune system, such as those with HIV, are highly susceptible to infection. The diagnosis of Gram-negative infections is often difficult, especially when these occur deep in the body. The resistance to antibiotics used to treat these infections makes the situation worse as the infection progresses undetected and so both new antibiotics and new ways of monitoring the success of treatment are urgently needed. This is a global crisis and only through an international collaborative scientific effort, will new antibiotics be discovered. An important aspect of this process is to build capacity in peptide based antibiotic drug discovery. A focus of such an endeavour is to provide scientists from historically disadvantaged backgrounds and institutions in SA the opportunity to be leaders in this field of research. Through this process, the training of the next generation of scientists is essential to ensure a continued success to find novel approaches to combat the perpetual threat of evolving bacterial infections, especially in the context of unique health care challenges in South Africa. One such approach is based on using antimicrobial peptides (AMPs), nature's own antibiotics which have remained effective throughout evolutionary history, but which have yet to make a breakthrough into clinical use. AMPs are key components of the innate immune system of a huge variety of living organisms, including humans, and have the ability to eradicate infection. Now, to show that AMPs can be developed as antibiotics for therapeutic application in patients we will learn how to modify them to increase their safety and stability. We will also ensure that they are more likely to work in patient by testing them in conditions that match more closely the patient infection setting. Existing methods of laboratory antibiotic testing are deficient as they often under- or over-estimate the potency of different types of antibiotic, most notably AMPs . As well as treating patients, we want to use AMPs to monitor their recovery or tell us when other antibiotics should be given. We will adapt imaging techniques, recently developed to study brain activity or find tumours and reveal the success of radio- and/or chemo-therapy. AMPs can be modified to carry a radioactive tracer and will circulate around the body before homing in on the bacteria causing infection. The tracer that is attached is used for either positron-emission tomography (PET) or single-photon emission computed tomography (SPECT) where a relatively low, and hence safe, dose of gamma rays is emitted. The intensity and location of the PET or SPECT signal can be mapped in the body in three dimensions to give the location and extent of any infection and to signal when, e.g. a localised infection starts to spread around the body. Since AMPs selectively target bacteria radiolabeling can provide a rapid, noninvasive method for infection imaging and with the correct antibiotic treatment, rapid patient recovery with reduced risk of antibiotic resistance development. Through Newton funding a UK and SA collaboration will be established to accelerate the innovative discovery of new AMP-based antibiotics. Through increased mobility and exchange of UK and SA researchers from UP, NWU and SMU, links between researchers in both countries will be strengthened and new partnerships will be developed with the possible establishment of a global pre-competitive drug discovery consortium. This process has a further benefit and that is the strengthening of the strategic relationship between the UK and South Africa.