Design and synthesis of lugdunin analogues as macrocyclic peptide antibiotics
Publication Date
July 24, 2024
Creator
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
ethesis
Thesis Type
PhD
Supervisors
Associated Schools / Departments
School of Pharmacy (UK)
eprints ID
77843
UoN Repository URI
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Ta-Chi, Su_PhD Thesis Submission_Corrected_04-04-2024.pdf
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