Effect of repetitive lysine–tryptophan motifs on the bactericidal activity of antimicrobial peptides

Abstract

Previous studies identified lysine- and tryptophan-rich sequences within various cationic antimicrobial peptides. In the present study, we synthesized a series of peptides composed of lysine (K)-tryptophan (W) repeats (KW)n (where n equals 2, 3, 4 or 5) with amidation of the C-terminal to increase cationicity. We found that increases in chain length up to (KW)4 enhanced the peptides’ antibacterial activity; (KW)5 exhibited somewhat less bactericidal activity than (KW)4. Cytotoxicity, measured as lysis of human red blood cells, also increased with increasing chain length. With (KW)5, reduced antibacterial activity and increased cytotoxicity correlated with greater hydrophobicity and self-aggregation in the aqueous environment. The peptides acted by inducing rapid collapse of the bacterial transmembrane potential and induction of membrane permeability. The mode of interaction of the peptides and the phosphate groups of lipopolysaccharide was dependent upon the peptides’ ability to permeate the membrane. Longer peptides [(KW)4 and (KW)5] but not shorter peptides [(KW)2 and (KW)3] strongly bound and partially inserted into negatively charged, anionic lipid bilayers. These longer peptides also induced membrane permeabilization and aggregation of lipid vesicles. The peptides had a disordered structure in aqueous solution, and only (KW)4 and (KW)5 displayed a folded conformation on lipid membranes. Moreover, (KW)4 destroyed and agglutinated bacterial cells, demonstrating its potential as an antimicrobial agent. Collectively, the results show (KW)4 to be the most efficacious peptide in the (KW)n series, exhibiting strong antibacterial activity with little cytotoxicity.Electronic supplementary materialThe online version of this article (doi:10.1007/s00726-012-1388-6) contains supplementary material, which is available to authorized users.

Structure-Activity Relationship Study of Novel Peptoids That Mimic the Structure of Antimicrobial Peptides

“…The MICs required to completely inhibit the growth of bacteria were within the range of 2 to 64 g/ml and revealed high to moderate antimicrobial peptoid activity throughout the library compared to that of structurally similar antimicrobial peptides, such as Bac8c indolicidin and omiganan (Table 1.) (23). This is in agreement with other reported MICs of peptides and peptidomimetics that contain lysine and tryptophan side chains (3,24,25). Peptoids 1, 7, and 15 are mimics of GN-2, GN-4, and GN-6 peptides, respectively (22), and the broad-spectrum antimicrobial activities were not improved upon making these structural changes (Table 1; see also Fig.…”

Antimicrobial activity and membrane-active mechanism of tryptophan zipper-like β-hairpin antimicrobial peptides

“…Therefore, considerable studies have been devoted for investigating the quantitative relationship between peptide chain length and antimicrobial activity; nevertheless, such studies are in poor agreement (Gopal et al 2013;Ma et al 2013). Several reports have indicated that peptide length is positively correlated with antibacterial and hemolytic activities (Liu et al 2007;Wiradharma et al 2011).…”

“…Furthermore, unlike conventional antibiotics which have specific intracellular targets that can be easily mutated by bacteria to gain resistance, the majority of AMPs exert their activities via the physical disruption of microbial membrane integrity to cause leakage of cytoplasmic components, leading to cell death (Ong et al 2013;Teixeira et al 2012). The physically destructive nature of microbial cell membranes is believed to prevent the development of microbial resistance toward AMPs because this would require microorganisms to alter their entire membrane lipid compositions (Gopal et al 2013). Due to these inherent advantages, the investigation and exploitation of AMPs have been regarded as a potential source of new therapeutic strategies for protection against multidrug-resistant bacteria.…”

Protective effect of a novel antifungal peptide derived from human chromogranin a on the immunity of mice infected with Candida krusei

“…Antimicrobial peptides (AMPs) are currently being studied extensively to assess their use as a new class of antimycotics because they possess broad-spectrum antimicrobial activities and may possibly thwart resistance (13)(14)(15). Chromogranin A is a major soluble protein of the adrenal medullary chromaffin granules and neurons, and is conservative in mammals (16,17).…”