Design and synthesis of novel antibacterial peptoids

Abstract

One of the current global challenges is tackling antibacterial multidrug resistance. The defense mechanisms of pathogenic bacteria and biofilm formation have significantly reduced the efficacy of conventional antibiotics. Though antimicrobial peptides (AMPs) have emerged as promising alternatives due to their unique mode of action, their clinical application is limited by issues such as toxicity and high production costs. To overcome these limitations, this project focused on designing and evaluating antibacterial peptidomimetics, specifically oligo-N-substituted glycine’s (peptoids) with amphiphilic structures.

In Chapter 2, a series of antibacterial cationic naphthyl-phenyl or naphthyl-indole-based peptoids were synthesized. Compounds 20a and 22 demonstrated the strongest antibacterial activity against 12 S. aureus strains with MIC of 3.2 µg mL−1 and 2.1 µg mL−1, respectively - compared to ciprofloxacin with MIC of 128-256 µg mL−1. Against E. coli, Compounds 12c and 13c were the most active peptoids (MIC = 12 µg mL−1).

In Chapter 3, the dimeric amino and guanidino peptoids were synthesized using aromatic moieties to enhance the activity. Amongst these, peptoid 10j showed excellent activity against S. aureus and E. coli with MIC values of 0.8 μg mL−1 and 6.2 μg mL−1, respectively. Also, compounds 10c and 10k were the best peptoids for disrupting S. aureus biofilm.

In Chapter 4, a series of substituted phenyl dimeric peptoids was designed by introducing various functional groups to modulate activity. Peptoids 11h and 11i emerged as the most potent, with MICs ranging from 0.75 to 2.6 μg mL−1 against S. aureus and 6.0 to 10.9 μg mL−1 against E. coli. Notably, peptoid 11f showed the highest biofilm-disrupting activity.

In the final chapter, peptoids 9j (from Chapter 3) and 10i (from Chapter 4) were subjected to guanidine modifications, generating a library of 30 substituted guanidino peptoids. The majority of these peptoids displayed excellent activity against S. aureus, with MIC values ranging from 1 to 8 μg mL−1, and showed consistent efficacy against E. coli, with average MICs between 4 and 8 μg mL−1. Peptoid 19b stood out as the most effective biofilm disruptor.

Throughout the project, the investigation into the mechanism of action revealed that the antibacterial effect might be attributed to the disruption of bacterial cell membranes. Additionally, hemolytic assays confirmed that the most active peptoids were non-toxic to mammalian red blood cells ( HC₅₀ = 25 - 50 μM).