The Carpet Model

The barrel-stave mechanism was found to be used by the non-cell-selective AMPs but not by those peptides that are selectively active on bacteria (Strahilevitz et al. 1994; Shai et al. 1990; Rapaport and Shai 1991,1992; Gazit et al. 1994; Pouny and Shai 1992; Shai 1994). Detailed mode-of-action studies suggested an alternative model, termed the carpet model or a detergent-like model (Pouny and Shai 1992; Gazit et al. 1995a,b).

Figure 7.4 depicts the four steps proposed to be involved in the carpet mechanism:

(1) The peptides bind, in a monomeric or oligomeric form, onto the surface of the negatively charged target membrane and cover it in a carpet-like manner.

(2) The peptides reorient themselves such that their hydrophobic face is toward the lipids and the hydrophilic face toward the phospholipid head groups.

(3) The peptides reach a threshold concentration.

(4) The peptides permeate/disintegrate the membrane by disrupting the bilayer curvature.

According to the carpet model, peptides are in contact with the phospholipid head group throughout the entire process of membrane permeation. An early step before the collapse of the membrane packing may include the formation of transient holes in the membrane. Such holes were described in the torodial model for pore formation or in the two-state model, in which the lipid bends back on itself like the inside of a torus (Matsuzaki et al. 1995; Ludtke et al. 1996; Heller et al. 1998; Huang 2000). Major differences between the carpet and barrel-stave models are: (1) the carpet model does not require recognition between membrane-bound peptide monomers; (2) in the carpet model peptides do not insert into the hydrophobic core of the membrane; and (3) the carpet model does not require a specific peptide structure. Based on the above, a major advantage of the carpet mechanism is that many peptides can fall within the criteria required, which indeed explains why thousands of peptides have antimicrobial activity regardless of their length, sequence and secondary structure.

Fig. 7.4. A cartoon illustrating the carpet model suggested for membrane permeation. The peptides reach the membrane as monomers or oligomers, followed by binding to the surface of the membrane with their hydrophobic surfaces facing the membrane and their hydrophillc surfaces facing the solvent (step A). After a threshold concentration of peptide monomers has been reached, the peptides permeate the membrane. This can be achieved In different ways, e.g. a detergent-like effect via the formation of non-organized transient pores (step B1), formation of organized transient or permanent toroidal pores (step B2) or hydrophobic pore/channel aggregates (B3) when the peptide Is very hydrophobic. The final stage in all cases may be membrane disintegration (step C)

Fig. 7.4. A cartoon illustrating the carpet model suggested for membrane permeation. The peptides reach the membrane as monomers or oligomers, followed by binding to the surface of the membrane with their hydrophobic surfaces facing the membrane and their hydrophillc surfaces facing the solvent (step A). After a threshold concentration of peptide monomers has been reached, the peptides permeate the membrane. This can be achieved In different ways, e.g. a detergent-like effect via the formation of non-organized transient pores (step B1), formation of organized transient or permanent toroidal pores (step B2) or hydrophobic pore/channel aggregates (B3) when the peptide Is very hydrophobic. The final stage in all cases may be membrane disintegration (step C)

The carpet mechanism described the mode of action of many other AMPs, such as dermaseptin natural analogues (Strahilevitz et al. 1994; Ghosh et al. 1997; La Rocca et al. 1999), cecropins (Gazit et al. 1994,1995a, 1996), the human AMP LL-37 (Oren et al. 1999), caerin 1.1 (Wong et al. 1997), trichogin GA IV (Monaco et al. 1999), androctonin (Hetru et al. 2000), diastereomers of lytic peptides (Shai and Oren 1996; Oren et al. 1997,1999; Fernandez-Lopez et al. 2001; Sharon et al. 1999; Oren and Shai 2000), Kassinatuerin-1 (Mattute et al. 2000), melittin in anionic lipids (Ladokhin and White 2001; Steinem et al. 2000), mastoparan X (Whiles et al. 2001), and apomyoglobin 56-131 peptide (Mak et al. 2001) (also reviewed in Zasloff 2002; Tossi et al. 2000; Bechinger 1999; Lohner and Prenner 1999; Epand and Vogel 1999; Dathe and Wieprecht 1999; Sitaram and Nagaraj 1999; Mor 2000). Note, however, that the carpet model is not characteristic only of AMPs, because short lytic peptides which are highly hydrophobic and are toxic to erythrocytes and fungi also act via the carpet mechanism (Oren et al. 1997,1999; Kustanovich et al. 2002).

In support of the membrane disintegration step, studies on the morphology of bacteria after treatment with AMPs that act via the carpet mechanism demonstrated the breakage of the bacterial membrane (Oren and Shai 1996, 2000; Shai and Oren 1996; Oren et al. 1997,1999). Figure 7.5 shows an example of electron

Fig.7.5. Electron micrographs of negatively stained E. coli D21 and P. aeruginosa untreated and treated with the diastereomers shown in Table 7.1 at 60% MIC and at their MIC. (a) untreated; (b) after treatment of E. coli with Amphipathic-1D (60% of MIC); (c) E.coli after treatment with Amphipathic-1D (at MIC); (d) untreated P. aeruginosa; (e) after treatment of P. aeruginosa with Amphipathic-ID (60%ofMIC); (f) P. aeruginosa treated with Amphipathic-1D (at MIC); (g) P. aeruginosa treated with Segregated-5D at the same concentration as indicated in (e)

Fig.7.5. Electron micrographs of negatively stained E. coli D21 and P. aeruginosa untreated and treated with the diastereomers shown in Table 7.1 at 60% MIC and at their MIC. (a) untreated; (b) after treatment of E. coli with Amphipathic-1D (60% of MIC); (c) E.coli after treatment with Amphipathic-1D (at MIC); (d) untreated P. aeruginosa; (e) after treatment of P. aeruginosa with Amphipathic-ID (60%ofMIC); (f) P. aeruginosa treated with Amphipathic-1D (at MIC); (g) P. aeruginosa treated with Segregated-5D at the same concentration as indicated in (e)

micrographs of negatively stained bacteria untreated and treated with diastere-omeric peptides listed in Table 7.1.

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