Chemical synthesis of novel antimicrobial peptides that target multidrug resistant bacteria

针对多重耐药细菌的新型抗菌肽的化学合成

• 批准号: 2275985
• 金额: --
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2275985
• 关键词: Chemical; synthesis; novel; antimicrobial; peptides

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.

抗菌素耐药性（AMR）对医疗保健质量乃至生命质量造成的威胁日益增加，这一点已得到充分证实1 - 3;据预测，到2050年，每年将有1000万人死于AMR。4由于缺乏新的抗微生物化合物的开发，以及它们在全球医疗保健中的过度使用。2在2000年至2010年期间，抗生素的药用增加了近40%。4再加上过去几十年抗生素的发现空白，通过大型制药公司减少或取消他们的抗菌药物研究和开发1，你会对问题的规模有一个感觉。显然，这不是一个可以现在就忽视、以后再解决的问题;在美国和欧洲，每年有5万人死于可治疗的细菌感染。4统计数据还告诉我们，每年有180万人死于结核病（TB）感染5，而结核病确实是可以治愈的。幸运的是，在这类药物化合物的研究领域中仍有许多未触及的途径。肽提供了一种有前途的AMC来源;它们提供了不同的结构能力，使得它们可以通过几种不同的途径杀死细菌，并且可以在使它们更具成本效益的同时微调特性。一些众所周知的抗生素属于多肽家族，如多粘菌素B6和万古霉素7。不幸的是，对这些抗生素的耐药性是已知的8，9，进一步强调需要更多的研究肽作为抗生素候选人。细菌可以通过多种方式被抗生素杀死，但也许最有效的策略是靶向参与基本细菌过程的酶。产生耐药性的可能性较小，因为细菌不会改变会阻碍其自身生存的过程。已知肽与参与DNA过程的一系列酶结合8，以及阻碍其他对生存重要的酶。肽合成在固体支持物上进行，称为固相肽合成（SPPS），是一个相对直接和有效的过程。在整个研究过程中，SPPS将用于合成抗菌肽的新型类似物，目的是使其对降解更稳定。传统的液相合成也将用于合成特定保护的氨基酸，以及克服可能出现的意想不到的障碍。一旦合成，新的类似物将通过高效液相色谱法纯化，并测试其对细菌酶的影响。这些类似物是基于设计指导的方法提出的，并且希望可以实现对多种细菌酶的抑制，使得这些肽可以被认为是有希望的抗生素候选物，其可能是种特异性的。同时与EPSRC的目标保持一致，为创新研究做出贡献。通过结合化学研究和应用生物技术的技能，我们希望增加科学界的知识，这样可能有助于解决日益严重的抗菌素耐药性问题。(1)临床感染2013，56，1685 - 1694中所述。(2)药物发现国家修订版2002，1（11），895 - 910. (3)1998，4，545 - 546。(4)J.奥尼尔，抗菌素耐药性报告，2014年。(5)世界卫生组织。2017，（WHO/EMP/IAU/2017.12）（6）J. Nat. Prod. 2017，80，1264 - 1274。(7)Biochem. Pharmacol. 2017，133，4 - 19. (8)国家生产部Rep. 2019，36，573 - 592。(9)J. Mol. 2009，385，1422 - 1432中所述。