Peptidomimetics are modified peptides aimed at retaining the efficacies of the original peptides while minimising or avoiding their drawbacks. An area where they hold great potential is that of antimicrobials because of the abundance in effective antimicrobial peptides (AMPs). Although several AMPs are already available, development of mimetics is of great importance to combat resistance. However, the process of design and development generally suffers from significant effort and time stemming from the size and complexity of peptides.

In this project, we develop upon a pharmacophore model for the design of peptidomimetics to target negatively-charged bacterial membranes^[1]. This model involves five building blocks: a hydrophobic scaffold (HS), two hydrocarbon linkers (HL), and two cationic groups (CG), resulting in bola-amphiphilic molecules with topology of CG-HL-HS-HL-CG. The modularity of our pharmacophore model allows for versatility and flexibility in designing new compounds, resulting in reduced developmental costs.

The cationic groups are often basic amino acids or groups that mimic the cationic property of AMPs for selectivity, while the hydrophobic scaffold can be treated as a non-natural amino acid that enables insertion into the lipophilic bacterial membrane. This results in a transmembrane conformation that perturbs the head groups and lipid tails of the membrane. We explore the effects of different building blocks on the antibacterial properties of the compounds, and the synergistic effects of such compounds with other AMPs against resistant Gram-negative bacteria.

We have obtained some promising results. The synthesised compounds successfully displayed antibacterial activities against both Gram-positive and Gram-negative bacteria, as well as demonstrated synergy with various AMPs against resistant Gram-negative bacteria. Preliminary tests confirmed their membrane-targeting mechanism.

The findings validate the hypothesis of this pharmacophore model and suggest the potential use of peptidomimetics as new antibiotics. This could accelerate the development of new antibacterial compounds to tackle the issue of antibiotic resistance.