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

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. <br/><br/>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.<br/><br/>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.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

Queen's University Belfast

Year dc:date.issued

2021

Author dc:creator

• Ballantine, Ross

Advisors dc:contributor.advisor

• Cochrane, Stephen
• Stevenson, Paul

• Antimicrobial peptides
• lipopeptides
• antimicrobial resistance
• peptides

Language dc:language

eng

Identifier

oai:pure.qub.ac.uk/portal:studenttheses/7f0b636f-6065-43d6-9d18-05bc0b661b1c

OAI identifier oai:identifier

oai:pure.qub.ac.uk/portal:studenttheses/7f0b636f-6065-43d6-9d18-05bc0b661b1c