Chemical synthesis of novel antimicrobial peptides that target multidrug resistant bacteria

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The ever increasing threat caused by antimicrobial resistance (AMR) to the quality of healthcare and indeed life, is well documented1-3; it is predicted that by 2050, 10 million people will die annually due to AMR.4 The issue is heightened by a lack of development of new antimicrobial compounds, as well as their overuse in global healthcare.2 Between 2000 and 2010 the medicinal use of antibiotics rose by nearly 40 %.4 Couple this to the antibiotic discovery void of the past few decades, perpetuated by big pharma reducing or removing their antimicrobial Research and Development1, then you get a sense of the scale of the issue. Clearly, this is not an issue that can be ignored now and addressed later; 50 000 are known to die each year across the USA and Europe due to treatable bacterial infections.4 Statistics also tell us 1.8 million people die annually due to Tuberculosis (TB) infections5, which indeed are curable.The need for research and development of new antimicrobial compounds (AMCs) is clear. Fortunately, there remains many untouched avenues in the research field for such medicinal compounds. Peptides provide a promising source of AMCs; they offer diverse structural capacity such that they can kill bacteria via several different avenues, and one can fine tune the properties at the same time as making them more cost-effective. Some well-known antibiotics belong to the polypeptide family, such as Polymyxin B6 and Vancomycin7. Unfortunately, resistance against these antibiotics is already known8,9, further highlighting the need for more research into peptides as antibiotic candidates.Bacteria can be killed in a variety of ways by antibiotics, but perhaps the most effective strategy is to target enzymes involved in essential bacterial processes. The chance of resistance arising is less likely, as the bacteria with refrain from altering processing that will hinder their own survival. Peptides are known to bind to a range of enzymes involved in DNA processes8, as well as hindering other enzymes important for survival.Peptide synthesis is carried out on a solid support, known as Solid Phase Peptide Synthesis (SPPS) and is a relatively straight forward and efficient process. Throughout this research, SPPS will be used to synthesise novel analogues of an antimicrobial peptide, with the aim of making it more stable to degradation. Conventional solution-phase synthesis will also be used to synthesise specifically protected amino acids, as well as to overcome the unexpected obstacles that can arise. Once synthesized, the new analogues will be purified by High Performance Liquid Chromatography and tested for their effects on bacterial enzymes. These analogues have been proposed based on a design guided approach and it is hoped that inhibition of a variety of bacterial enzymes can be achieved such that these peptides can be considered promising antibiotic candidates, which could potentially be species-specific.This research is aimed to aid the knowledge of antimicrobial peptides in the field of Biological Chemistry, while aligning itself with the EPSRC's objective to contribute towards innovative research. By combining skills from both chemical research and applying biological techniques, we hope to add to the knowledge of the scientific community, such that it may be help tackle the growing problem of antimicrobial resistance.(1) Clin. Infect. Dis. 2013, 56, 1685-1694. (2) Nat. Rev. Drug Discov. 2002, 1 (11), 895-910. (3) Nat. Med. 1998, 4, 545-546. (4) J. O'Neill, Antimicrobial Resistance Report, 2014. (5) World Health Organization. 2017, (WHO/EMP/IAU/2017.12) (6) J. Nat. Prod. 2017, 80, 1264-1274.(7) Biochem. Pharmacol. 2017, 133, 4-19. (8) Nat. Prod. Rep. 2019, 36, 573-592. (9) J. Mol. Biol. 2009, 385, 1422-1432.