## 3 Antibiofilm Peptidomimetics  
When straddling towards the post antibiotic era, AMPs were viewed as the solution. However, antimicrobial peptides possess a number of drawbacks such as susceptibility to protein degradation, salt/pH sensitivity etc. Peptidomimetics, on the other hand, have proved to overcome stability issues while retaining activity profile of original peptides. However, despite their advantages, there are only a few peptidomimetics in the literature tested for antib Biofilm potency. One of the first mimetics to be reported on in respect to anti-biofilm properties was a mimetic containing poly-\(N\)-substituted glycine residues, or a peptoid. In contrast to peptides, the peptoids are substituted at the amide nitrogen and cannot form intermolecular hydrogen bonds to stabilize secondary structures [74]. The 12-mer peptoid sequence, Peptoid 1, composed of alternating Nlys (\(N\)-(4-aminobutyl) glycine) and Nspe (\(N\)-(1-phenylethyl) glycine) units (Table 3) and a lipidated analogue of it, Peptoid 1-C134 mer, were analyzed in a stationary biofilm assay with _P. aeruginosa_. At MICs concentrations of Peptoid 1 and Peptoid 1-C134 mer, resulted in a significant reduction in bacterial biomass and cell viability of the biofilm [75]. In other words, both Peptoid 1 and Peptoid 1-C134 mer killed bacterial cells within biofilm. The authors propose that Peptoid 1 oligomerization via aromatic side chain interactions promotes and increased local Peptoid 1 concentration at the cell membrane, thus effectively disrupting the bacterial biofilm. Conversely, Peptoid 1-C134 mer is suggested to disrupt the hydrophobic exopolysaccharide and penetrate deeper into the matrix as a result on the lipid tail, thus efficiently reducing cell viability. A similar effect of lipidation has been demonstrated in a family of lipo-cyclic-\(\gamma\)-AAepeptides (Table 3), resulting in comparable or enhanced performance compared to ciprofloxacin in the prevention of biofilm formation for both Gram-positive and Gram-negative bacteria [76]. The most potent peptidomimetic in this family, YL-36, exhibited up to 80% and 70% reduction in the formation of the _P. aeruginosa_ and MRSE (methicillin resistant _Staphylococcus epidermidis_) biofilms. Combined with earlier discussed results, lipidated antimicrobial peptidomimetics are suggested to be more effective in the biofilm prevention, possibly due to the existence of lipid tails, which might retard the growth of biofilms. Another well-studied peptidomimetic approach has been to make peptide-peptide hybrids. Using this strategy and alternating lysine units and Nspe units, resulted in a sequence with similarities to Peptoid 1, though with a higher charge to hydrophobicity ratio. The hybrid HDM-4 (Table 3) exhibited strong anti-biofilm activity at the same sub-MIC level concentration toward four separate Gram-negative bacteria, as also concluded for cationic anti-biofilm peptides [77]. For all tested bacterial strains, the biomass was reduced by \(>\)90% at 0.125-0.53 ug/mL planktonic cell MIC. A similar peptide-peptoid hybrid has been designed with the use of \(\beta\)-peptide elements rather than Nspe, thus introducing more flexibility along the backbone and a more elongated structure. Testing this \(\beta\)-peptoid-peptide hybrid 4d (Table 3) demonstrated that it was able to reduce cell viability by 80-85% at 1-4 \(\times\) MIC [78]. However, 4d managed to cause 78% of reduction in living biomass only at 400 \(\times\) MIC concentration. Interestingly, in the other study a similar alternating scaffold was utilized where Nspe residues were replaced with \(N\)-alkyl/aryl pyrazole (Py) residues and lysine was substituted with arginine to maintain the necessary cationicity. One of the most potent examples of pyrazole-derived peptidomimetics is ultra-short peptidomimetic Py11 that was able to inhibit 90% biofilm development of multidrug-resistant _P. aeruginosa_ at 16 ug/mL compared to LL-37 that reached the same result at 64 ug/mL [79].