SYNTHESIS AND STRUCTURE ACTIVITY RELATIONSHIP OF TEIXOBACTIN ANALOGUES

Malkawi, Ruba (2021) SYNTHESIS AND STRUCTURE ACTIVITY RELATIONSHIP OF TEIXOBACTIN ANALOGUES. PhD thesis, University of Liverpool.

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Abstract

Multi-drug resistant bacteria that are primarily unresponsive towards the available marketed antibiotics presents a threat to global health, leading to an increase in mortality and morbidity rate. Today, more than 700,000 people die annually as a consequence to the bacterial infections. This number is expected to rise to 10 million by 2050. New effective antibiotics are still not available, and few are under development as the return on investment is considered low compared to the medications utilised for chronic diseases such as, asthma, and cancer. According to the World Health Organisation (WHO), the world tends to be moving to the post-antibiotic era in which previously treatable bacterial infections are becoming more fatal. As a result of the global spread of bacterial resistance, the researchers collaborated their effort towards finding alternative antimicrobial agents. Antimicrobial peptides are generated by most of the living organisms as part of their immune system, which makes them an interest to synthetic chemists to produce novel antimicrobials. One such antimicrobial is the recently discovered novel natural product teixobactin, which has showed promising data and known to act as a dual target as its mechanism of action. Teixobactin is a macrocyclic depsipeptide presenting excellent activity against Gram-positive bacteria, by targeting lipid II and III to inhibit bacterial cell wall biosynthesis. Teixobactin consists of a 13 membered depsipeptide macrocycle which is constituted by several proteinogenic and one non-proteinogenic amino acid (Enduracididine). Furthermore, the linear tail of teixobactin also consists of seven amino acids of different configuration. In this research, five different projects were conducted on teixobactin based upon the structure-activity relationship (SAR). Each project encompasses a new design of teixobactin synthesis with a group of teixobactin analogues synthesised according to that protocol. Moreover, each project contains antibacterial study to explore the potency of the newly synthesised teixobactin analogues. The first chapter involves the background of the antibiotics in addition to the challenges it faces currently. Moreover, the first chapter introduces a definition of the antimicrobial peptides, especially teixobactin and its discovery and as well as a comprehensive literature review of the research that has been conducted on teixobactin so far. The second and third chapters present a group of analogues where the natural teixobactin ester bond was replaced by disulphide-bridge or amide bond to understand the role v of the ester bond towards its biological activity. Furthermore, third chapter also shows the effect of macrocycle expansion of the teixobactin on its antibacterial activity. The fourth presents the effect of the inclusion of quaternary and ternary amino compounds to the teixobactin structure, where they are coupled to various suitable positions of teixobactin. The fifth chapter chapter shows the impact of Enduracididine10 replacement by cysteine attached with variable alkyl groups.. The sixth chapter contains twenty-eight new teixobactin analogues with different non-proteogenic amino acids in various tolerable positions to explore the antibacterial activity of teixobactin and further investigate the structure-activity relationship (SAR). The last chapter involves a general summary of the work and perspective related to teixobactin. In summary, synthetic studies based on natural products showing antibacterial activity have been conducted towards the development of a new potent teixobactin analogue. Additionally, this whole new research could be potentially useful to develop a further understanding of SAR study of teixobactin.

Item Type:	Thesis (PhD)
Divisions:	Faculty of Health and Life Sciences
Depositing User:	Symplectic Admin
Date Deposited:	08 Feb 2022 15:06
Last Modified:	18 Jan 2023 21:32
DOI:	10.17638/03134463
Supervisors:	Singh, Ishwar ORCID: 0000-0001-7822-1063 Hope, William
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3134463