*2.3.1 Antimicrobial peptides*

Antimicrobial peptides (AMPs) that are crucial players of innate immunity are reported to prevent biofilm formation in different pathogens. AMPs with antibiofilm activity are either natural or synthetic. The human cathelicidin peptide, LL-37, has been demonstrated to have antibiofilm activity in case of *P. aeruginosa* (at a concentration of 0.5 μg/mL), while the minimum inhibitory concentration for planktonic cells was 64 μg/mL [90]. In this study, it was reported that LL-37 was able to interfere with the adherence of microbial cells, enhancing twitching motility and downregulation of genes required for biofilm formation via affecting quorum sensing systems (Las and Rhl) [90]. Furthermore, such peptide was shown to prevent biofilm formation in *E. coli* and *S. aureus* [91]. The mouse cathelicidinderived peptide AS10 was reported to exhibit antibiofilm activity in *Candida albicans* [92]. The synthetic cathelicidin-derived peptides; peptide 1018, DJK5 and DJK6, were reported to prevent biofilm formation in addition to enhancement of biofilm dispersion via prompting the hydrolysis of nucleotide signaling systems, and therefore, leads to its depletion in bacteria [93].

Another synthetic peptide, S4(1–16) M4Ka, has been found to inhibit biofilm formation and detach bacterial cells in *P. aeruginosa* [94]. The human β-defensin 3 (hBD-3) was found to inhibit the expression of *icaA*, *icaD* and *icaR* genes of *Staphylococcus epidermidis,* thus interfering with biofilm formation, where biofilm formation in *Staphylococci* is dependent on the synthesis of the polysaccharide intercellular adhesin PIA encoded by *icaADBC* locus [95]. Another example of human AMP with antibiofilm activity in *S. epidermidis*, is the liver-derived hepcidin 20. This peptide can inhibit extracellular matrix formation of biofilms via targeting PIA [95].

The natural AMP piscidin-3, obtained from fish, exhibits nucleosidase activity and can degrade extracellular DNA of *P. aeruginosa* [96]. Another example of natural AMP, that possesses antibiofilm activity, is esculentin, which is obtained from frog's skin. It acts by permeabilization of the cellular membrane of *P. aeruginosa* PAO1 cells in the biofilm [97]. A synthetic peptide P1, derived from a tick antifreeze protein, significantly inhibited biofilm formation in *Streptococcus mutans*. Such peptide reduced biofilm biomass by about 75% in microtiter plates and *in vitro*  tooth models [98].
