Structural and mechanistic studies on antimicrobial peptides that target multi-drug resistant bacteria

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Antimicrobial resistance is a growing threat that will have profound effects on global health and the economy. In order to avoid a worst-case scenario, there is a need to develop structurally distinct classes of antibiotics. Herein, the synthesis of cyclic lipopeptides based on the tridecaptins is reported. In particular, analogues where residues D-Trp5 and Phe9 were substituted for D-Cys and Cys respectively were synthesized and cross-linked with various benzylic linkers of various sizes. Ortho-xylyl, meta-xylyl and para-xylyl cross-linked Oct-TriA1 maintained strong activity against Escherichia coli and other ESKAPE pathogens (including carbapenem-resistant Acinetobacter baumannii). Interestingly, these analogues were resistant to enzymatic degradation in the presence of recently reported D-stereoselective peptidases.

Secondly, brevicidine represents a promising candidate for further research and development and this ultimately relies on a synthetic route to acquire sufficient material. The first reported synthesis of brevicidine is reported within this thesis. Briefly, an on-resin approach was used to pre-form the sensitive macrocyclic ring with a modified Yamaguchi esterification. Subsequent Fmoc-SPPS and global cleavage yielded the desired peptide in impressively high yields. With a synthetic route in hand, early structure-activity relationship studies were commenced. Subtle alterations did not ablate the antimicrobial activity while theoretically stabilizing the peptide towards in vivo hydrolysis.

Finally, attempts were made to synthesize various lipid tails to install on the depsipeptide globomycin. The natural and non-allo versions of linear globomycin were synthesized and tested using a recently developed fluorescence resonance energy transfer (FRET) assay developed by the Caffrey group.
Date of AwardJul 2021
Original languageEnglish
Awarding Institution
  • Queen's University Belfast
SponsorsNorthern Ireland Department for the Economy
SupervisorStephen Cochrane (Supervisor) & Paul Stevenson (Supervisor)

Keywords

  • Antimicrobial peptides
  • lipopeptides
  • antimicrobial resistance
  • peptides

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