Abstract
Circular dichroism and 1H NMR were used to investigate the interactions of a series of synthetic antimicrobial peptides (AMPs) with lipopolysaccharides (LPS) isolated from Pseudomonas aeruginosa and Klebsiella pneumoniae. Previous CD studies with AMPs containing only three Tic-Oic dipeptide units do not exhibit helical characteristics upon interacting with small unilamellar vesicles (SUVs) consisting of LPS. Increasing the number of Tic-Oic dipeptide units to six resulted in five analogues with CD spectra that exhibited helical characteristics on binding to LPS SUVs. Spectroscopic and in vitro inhibitory data suggest that there are two possible helical conformations resulting from two different AMP-LPS binding mechanisms. Mechanism one involves a helical binding conformation where the AMP binds LPS very strongly and is not efficiently transported across the LPS bilayer resulting in the loss of inhibitory activity. Mechanism two involves a helical binding conformation where the AMP binds LPS very loosely and is efficiently transported across the LPS bilayer resulting in an increase in inhibitory activity. Mechanism three involves a nonhelical binding conformation where the AMP binds LPS very loosely and is efficiently transported across the LPS bilayer resulting in an increase in inhibitory activity.
Highlights
Because of their novel mechanisms of antibiotic activity, which generally involves some type of membrane disruption, antimicrobial peptides (AMP) have the potential to be developed into useful antibiotic therapeutic agents
We previously reported that increasing the number of Tic-Oic dipeptide units from three to six without the incorporation of residues A, B, C, and D in AMPs 70 or 22 resulted in a dramatic loss in activity against all of the Gram-negative bacteria tested, compared to the analogues containing three Tic-Oic dipeptide units (e.g., AMP 23: Ac-GF-Tic-Oic-GKTic-Oic-GF-Tic-Oic-GK-Tic-KKKK-CONH2) [78]. (Please see Table 3 for in vitro inhibitory activity of the AMPs investigated in this study)
In the presence of LPS isolated from P. aeruginosa, the CD spectra of AMPs 22, 70, 74, 75, and 77 exhibit helical-like features, while in the presence of LPS isolated from K. pneumoniae, the CD spectra of AMPs 22, 70, 75, and 77 exhibit helical-like features
Summary
Because of their novel mechanisms of antibiotic activity, which generally involves some type of membrane disruption, antimicrobial peptides (AMP) have the potential to be developed into useful antibiotic therapeutic agents. The antibacterial and anticancer activity of the antimicrobial peptides LL-37 [20, 21], human beta-defensin-3 [21, 22], and other AMPs [21] has been extensively investigated and reviewed in the literature. Some researchers have suggested that antimicrobial activity is not the primary function of mammalian AMPs such as the defensins [20]. Their primary function may involve immunomodulatory processes in controlling the interaction
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