## 4 Antimicrobial Agents
### Antibiofilm Peptides  
Antimicrobial peptides (AMPs) are a type of innate defense mechanism in different eukaryotes which was first discovered by [PERSON] and [PERSON] in the 1960s. AMPs are cationic and hydrophobic residues containing molecules that can interact with various microorganisms such as bacteria, fungus, protozoa, and some enveloped viruses [98; 99; 100]. Since AMPs have low antigenicity and rapid killing effect in comparison to conventional antibiotics, it has been showing momentous potential in recent years [101]. Studies show sub-minimal inhibitory concentration (MIC) of some AMPs is also able to inhibit biofilm in various pathogens, thus these peptides are termed antibiofilm peptides (ABPs) [102]. Antimicrobial peptides display a wide range of antibiofilm effects by (1) cleavage of peptidoglycan, (2) change of membrane permeabilization or membrane potential, (3) neutralization or disassembly of lipopolysaccharideaccharides, (4) inhibition of cell division and cell survival, (5) modulate the synthesis of adhesion molecule synthesis and function, and (6) repression of the stringent response of the bacteria [54; 103]. Some ABPs and their mechanisms for biofilm inhibition or dispersal are given in Table 5.  
AMPs such as nisin and bovicin HC5 reduced the _S. aureus_ adhesion to the polystyrene surfaces and altered the cell as well as polystyrene surface hydrophobicity. These AMPs also changed the biofilm-related gene expressions in planktonic cells [104]. On the other hand, a popular human cathelcidin AMP, LL-37, and indolicidin were known to inhibit _P. aeruginosa_ biofilm formation. It was likely achieved by inhibiting the transcription of Las and Rhl QS systems [105; 106]. LL-37 also inhibits biofilm formation of _P. aeruginosa_ by upregulating the expression of genes needed for type IV pili biosynthesis and function [105]. Likewise, peptide 1037 efficiently inhibits biofilm production by the Gram-positive _L. monocytogenes_ and Gram-negative pathogens _Burkholderia cencopercia_ and _P. aeruginosa_. Peptide 1037 directly reduced biofilm production by decreasing swarming and swimming motilities, inducing twitching motility, and downregulation of several genes related to biofilm production [106]. [PERSON] et al. found an effective anti-biofilm peptide 1018 which could bind and degrade (p)ppGpp, a crucial signal required for the formation of biofilm [102]. Peptide 1018 treatment completely prevented biofilm production at much lower concentrations, which did not alter planktonic growth and also caused degradation of mature biofilms in _E. coli_, _A. baumannii_, _P. aeruginosa_, _Klebsiella pneumoniae_, MRSA, _S. Typhimuriumium_, and Burkholderia cencopercia [102]. D-enantiomeric protease-resistant peptides DJK-5 and DJK-6 could reduce (p)ppGpp in biofilms of _P. aeruginosa_ to a greater amount than 1018 [107]. Apidaecin, pyrrhocoricin, and drosocin are 18-20 amino acid, proline-rich residues that were initially obtained from insects. These AMPs attack a target microbial protein in a stereospecific manner. They interact with the bacterial heat-shock protein DnaK by inhibiting chaperone-assisted protein folding and limiting the DnaK ATPase activity [108; 109; 110]. The peptide antibiotic microcin B17 (MccB17) is the first peptide known to repress a type II DNA topoisomerase activity. MccB17 blocks _E. coli_ DNA gyrase by trapping an enzyme-DNA cleavable complex [111]. PR-39, an AMP which was obtained from the upper portion of a pig's small intestine, could kill growing bacteria faster than non-growing cells. It is suggested that PR-39 kills bacteria by stopping protein and DNA synthesis [112]. Some antimicrobial peptides polarize and permeabilize the cell membrane and finally cause membrane disruptions. Esculentin (Esc (1-21) is the AMP derived from the frog skin. It could breach the cytoplasmic membrane of Gram-negative bacteria for example _P. aeruginosa_ PAO1 inside the biofilms and lead to a discharge of \(\beta\)-galactosidase.