Saudi Cultural Missions Theses & Dissertations
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Item Restricted Identification of Antimicrobial Peptides against Gram-negative Bacteria(Saudi Digital Library, 2023-12-20) Alsaab, Fahad; Van Hoek, MoniqueAntibiotic resistance in bacteria has been rising due to excessive and improper use of antibiotics. There is a pressing need to find alternative approaches to tackle this issue. Unconventional antimicrobials have been proposed to combat multidrug resistant (MDR) bacteria. Antimicrobial peptides (AMPs) are promising compounds for fighting bacterial infections. AMPs are a cationic polypeptide chain that can target microorganisms, including bacteria. In this work, three approaches of peptide design have been implemented to generate novel peptides with a focus on gram-negative bacteria. Computational-aided positional analysis method was utilized to generate peptides based on pre-existing dataset of Acinetobacter (A.) baumannii-active peptides to target multidrug resistant (MDR) A. baumannii. The output resulted in the generation of five peptides, HRZN-13 to -17. HRZN-15 peptide had the strongest antibacterial and antibiofilm activity against MDR A. baumannii among HRZN peptides. However, it was toxic to human red blood cells (RBCs) and Galleria mellonella (waxworms). Rational design created a novel sequence GATR-3 from a cryptic peptide that was isolated from American alligator, which we characterized in this study against A. baumannii. GATR-3 exhibited potent antimicrobial activity against a panel of MDR A. baumannii strains. The most exciting finding was that it inhibited biofilm formation as well as eradicated preformed biofilm in this wound-infecting pathogen. GATR-3 did not cause toxicity in hepatocytes, human RBCs and G. mellonella. It also demonstrated host-directed activity, inducing migration of macrophages. The third method that was employed in this study is chemical modification of naturally occurring peptides. The human cathelicidin LL-37 peptide was dissected to find smaller fragments that have antibiofilm activity against Francisella novicida. KR-12 was the smallest fragment tested that exhibited antibiofilm activity but failed to inhibit growth of F. novicida, indicating it’s antibiofilm activity. Therefore, chemical staples were introduced on KR-12 and KR-16 fragments to support their secondary structure conformations and potentially increase their stability or activity. Stapled peptides successfully demonstrated improved growth-inhibitory effect of F. novicida, compared to the native peptides, with minimal toxicity towards human RBCs. All the peptide design methods presented in this dissertation led to the production of novel peptides with activity against gram-negative bacteria.51 0