Synthetic Antimicrobial Peptides Exhibit Two Different Binding Mechanisms to the Lipopolysaccharides Isolated from Pseudomonas aeruginosa and Klebsiella pneumoniae

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.

OmpA Binding Mediates the Effect of Antimicrobial Peptide LL-37 on Acinetobacter baumannii

“…Most studies suggest that AMPs act on Gram-negative bacteria through their surface LPS molecules [ 46 – 48 ]. However, several studies have emphasized the interaction between AMPs and OMPs.…”

Romo1-Derived Antimicrobial Peptide Is a New Antimicrobial Agent against Multidrug-Resistant Bacteria in a Murine Model of Sepsis

“…Indeed, some AMPs have the ability to interact with endotoxins such as lipopolysaccharide, alleviating systemic inflammation (42). It has been reported that positively charged amino acids in the AMP (R, K, and H) can neutralize negatively charged lipid A, and the hydrophobic region of AMP can interact with acyl chains of lipid A (43). AMPR-11 contains two positively charged amino acids (K58 and R78) and a hydrophobic region (F70 to I77), which might be important for interacting with the negatively charged head group and hydrophobic acyl chains of lipid A, respectively.…”

A bovine myeloid antimicrobial peptide (BMAP-28) and its analogs kill pan-drug-resistant Acinetobacter baumannii by interacting with outer membrane protein A (OmpA)

“…Most studies exhibit that AMPs act on gram-negative bacteria through their surface lipopolysaccharide (LPS) molecules. [ 25 – 27 ] A previous study reported that LL-37 may bind to A baumannii LPS with high affinity, but its bactericidal activity is not LPS-dependent. [ 28 ] However, several studies have emphasized the interaction between AMPs and bacterial outer membrane proteins (OMPs).…”