## 2 Synthetic Antimicrobial Peptides
Introduction of sulfonamide groups has been also investigated to exploit their bio-active properties, enhance their proteolytic stability and hydrogen bonding ability [42]. Another approach to improve the half-life of peptides in vivo is to synthesize them as dendrimers around a residue or a linear polymer core [43]. These multiple antigen peptides (MAP) developed by [PERSON] and colleagues [44] are mainly constituted by a lysine core to which peptide chains are attached [45]. The number of bi-, tri-, tetra and more sequence patterns define the multivalency of those peptides and confers an increased cationic charge as well as hydrophobic groups. The steric hindrance given by the bulk, firstly, limit the access to the proteolytic site [46; 47] and, secondly, seems to improve their activity by increasing the local concentration of peptide units with membranolytic activity [48]. Peptide structure is a pivotal point for the interaction with the membranes: the cationic charge allows the initial binding to a negatively charged layer; afterwards, while amphipplicity is necessary for membrane perturbation and peptide uptake, the hydrophobic groups are responsible for the carving [49]. Studies on the mechanism of action would divide the AMPs in two categories: _membrane disruptive_[50; 51] and _non-membrane disruptive_ (activity on other targets) (Figure 1) [52; 53]. Figure 1: AMPs broad-spectrum antimicrobial activity. **(a)** Primarily, AMPs’action is based on their action on cytoplasmic membranes, i.e., perturbation or disruption. However, in presence of Gram-negative bacteria **(A)** AMPs have to firstly cross the outer phospholipid membrane and secondly traverse the peptidoglycan layer before reaching the inner membrane. In Gram-positive bacteria **(B)** they navigate through the thick cell wall of peptidoglycan and in fungi **(C)**, they encounter mannitol proteins, glucans and chitin prior to access to the cytoplasmic membrane. Once reached the phospholipid bilayer, they induce perturbation via pore formation following either **(D)** (i) _carpet-like_, (ii) _barrel-stave_ or (iii) or _toroidal pore_ model depending on the peptide composition. **(b)** Besides pore formation, some AMPs bind some components and receptors on the extracellular side of the membrane, i.e., Toll-like receptors; others manage to enter the cytosol through direct penetration in vesicles or channels thus destabilizing the permeability and activating the inflammatory cytokines cascade. Intracellularly, they could also interfere with DNA or RNA leading to degradation and cell death. They may also affect mitochondrial activity or protein synthesis by targeting ribosome subunits or protein folding. In the case of bacterial cell wall, they can prevent elongation of peptidoglycan chains or hinder teichoic and teichuronic binding acids to amidaases. Cell wall components inhibition will promote cell autolysis. In the extracellular space, AMPs can sequestrate LPS reducing the impact of endotoxins on the host’s immune response. In fungal cells, AMPs can intervene on glucan synthesis thus blocking the building pieces of their wall. Further inhibitory action on biofilm matrix impairs the _quorum sensing_ and improves the susceptibility of the single pathogens in both bacterial and fungal communities.