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Su, Ta-Chi (2024) Design and synthesis of lugdunin analogues as macrocyclic peptide antibiotics. PhD thesis, University of Nottingham.

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Abstract

Due to the overuse of antibiotics, bacteria have become increasingly resistant to many different antibiotics, resulting in antibiotic-resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA). It also makes the clinical treatment of bacterial diseases more difficult and leads to an increased mortality rate. The development of new classes of antibiotics has remained stagnant for a long time. In 2016, lugdunin, a new natural product from Staphylococcus lugdunensis which is presented in the human nostrils, was found to display potent antimicrobial activity against antibiotic-resistant strains of S. aureus (MIC = 1.5 µg/ml against MRSA). Thus, the project aims to design a focused series of lugdunin analogues and to determine their antimicrobial activities against different strains of S. aureus.

To synthesize lugdunin and its analogues, the Fmoc-based solid phase peptide synthesis (FmocSPPS) was used. Moreover, various types of solid supports (resin) were investigated and used to optimize the reaction. For the total synthesis of lugdunin and analogues thereof, threonineglycine (TG) resin was used as the most effective resin due to several advantages, such as high yields and simple operation. A modified TG resin was then prepared by the pre-loading of different Fmoc-amino aldehydes, which in turn were prepared from their corresponding Fmocamino acids by a one-pot procedure involving 1, 1'-carbonyldiimidazole (CDI)-activation followed by diisobutylaluminium hydride (DIBAL-H)-mediated reduction.

To determine the importance of each amino acid residue to the antimicrobial activity, alanine scanning was first introduced. Then, to establish a preliminary structure-activity relationship (SAR), several analogues were synthesized, such as the installation of modified amino acids, including D-phenylalanine and D-tryptophan at position-6 and L-norvaline, L-norleucine, N-methyl-L-valine, N-methyl-L-leucine, L-tryptophan, L-cyclopropylalanine and L-homoleucine at position 7.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Chan, Weng
Keywords:	peptide antibiotics, antibacteria, lugdunin analogues
Subjects:	Q Science > QR Microbiology > QR 75 Bacteria. Cyanobacteria R Medicine > RM Therapeutics. Pharmacology R Medicine > RS Pharmacy and materia medica
Faculties/Schools:	UK Campuses > Faculty of Science > School of Pharmacy
Item ID:	77843
Depositing User:	Su, Ta-Chi
Date Deposited:	20 Nov 2025 10:50
Last Modified:	20 Nov 2025 10:50
URI:	https://eprints.nottingham.ac.uk/id/eprint/77843

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