Antimicrobial activity of synthetic analogues of human β-defensins

Ijakipour, Hanieh (2023). Antimicrobial activity of synthetic analogues of human β-defensins. University of Birmingham. Ph.D.

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Abstract

The emergence of antibiotic resistant bacteria calls for the advancement in a new class of drug and drug discovery. Antimicrobial peptides (AMPs) have been shown to have a broad spectrum of activity against pathogens such as bacterial, viral, and fungal infections. Although this class of molecules shows a broad spectrum activity, they often show poor bioavailability and stability in vivo. The key to resolve such complex problems is to either design an antimicrobial peptide that does not show degradation pattern or by performing post-synthesis modifications such as cyclisation or N-terminal acetylation or to design a peptide that when degraded retains its antimicrobial activity.
To design an effective antimicrobial peptide with a broad spectrum activity against Gram-positive and Gram-negative bacteria, Human Beta Defensin 1 (hBD1) and Human Beta Defensin 3 (hBD3) were chosen as reference sequences. These peptides were chosen due to the lack of research done on Beta defensins and their broad spectrum of activity against a variety of pathogens. The rational behind the design of peptides was to remove the Cysteine residues in the original sequence of the defensins to ease the synthesis process, the sequences were then shortened by removal of uncommon amino acids in the sequence of antimicrobial peptides found in ACP database. The sequences were then modified to show a minimum similarity of 40% to the original antimicrobial sequence.
To assess the activity of these peptides they were tested against different bacteria and the results determined that HBD-mod8 based on hBD1 showed comparable antimicrobial activity to the positive control (antibiotic) against different bacterial species. To asses the stability and cytotoxicity of this peptide, it was tested against human serum and human Hela cells. To find the motif responsible for the activity of this peptide an alanine scan was set-up determining the motifs that were crucial for the activity of this peptide. Results showed the degradation of the peptide into a smaller fragment was the key in the antimicrobial activity and it showed a non toxic effect towards the human cells.
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Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):