Bacterial Cell Wall Compounds as Promising Targets of Antimicrobial Agents I. Antimicrobial Peptides and Lipopolyamines

Abstract

The first barrier that an antimicrobial agent must overcome when interacting with its target is the microbial cell wall. In the case of Gram-negative bacteria, additional to the cytoplasmic membrane and the peptidoglycan layer, an outer membrane (OM) is the outermost barrier. The OM has an asymmetric distribution of the lipids with phospholipids and lipopolysaccharide (LPS) located in the inner and outer leaflets, respectively. In contrast, Gram-positive bacteria lack OM and possess a much thicker peptidoglycan layer compared to their Gram-negative counterparts. An additional class of amphiphiles exist in Gram-positives, the lipoteichoic acids (LTA), which may represent important structural components. These long molecules cross-bridge the entire cell envelope with their lipid component inserting into the outer leaflet of the cytoplasmic membrane and the teichoic acid portion penetrating into the peptidoglycan layer. Furthermore, both classes of bacteria have other important amphiphiles, such as lipoproteins, whose importance has become evident only recently. It is not known yet whether any of these amphiphilic components are able to stimulate the immune system under physiological conditions as constituents of intact bacteria. However, all of them have a very high pro-inflammatory activity when released from the cell. Such a release may take place through the interaction with the immune system, or with antibiotics (particularly with those targeting cell wall components), or simply by the bacterial division. Therefore, a given antimicrobial agent must ideally have a double character, namely, it must overcome the bacterial cell wall barrier, without inducing the liberation of the pro-inflammatory amphiphiles. Here, new data are presented which describe the development and use of membrane-active antimicrobial agents, in particular antimicrobial peptides (AMPs) and lipopolyamines. In this way, essential progress was achieved, in particular with respect to the inhibition of deleterious consequences of bacterial infections such as severe sepsis and septic shock.

Antimicrobial peptides and their potential application in inflammation and sepsis

“…Thus, human binding proteins, such as LPS binding protein (LBP) and CD14, are impeded from binding to LPS epitopes, the charged head groups, and thus cannot initiate the inflammatory reaction. It has been found, furthermore, that the peptides still exert their effect when they are added in a time-delayed mode, i.e., when they are administered up to 3 hours after LPS addition [36]. This observation is indicative of a membrane process of the interaction, in accordance with recent findings that the peptides readily intercalate into membranes made from phosphatidylcholine and phosphatidylserine as characteristic of eukaryotic cells [34].…”

Antimicrobial Peptides and their Potential Application in Inflammation and Sepsis

“…Th us, human binding proteins, such as LPS binding protein (LBP) and CD14, are impeded from binding to LPS epitopes, the charged head groups, and thus cannot initiate the infl ammatory reaction. It has been found, furthermore, that the peptides still exert their eff ect when they are added in a time-delayed mode, i.e., when they are administered up to 3 hours after LPS addition [36]. Th is observation is indicative of a membrane process of the interaction, in accordance with recent fi ndings that the peptides readily intercalate into membranes made from phosphatidylcholine and phosphatidylserine as characteristic of eukaryotic cells [34].…”

Polyphenolic Extract from Maple Syrup Potentiates Antibiotic Susceptibility and Reduces Biofilm Formation of Pathogenic Bacteria

“…The outer membrane is an advanced barrier shielding the bacterial cell against external antimicrobial compounds (53). To achieve the target cytoplasmic membrane, antimicrobial agents must overcome the barrier of the outer membrane in Gram-negative bacteria (54). This involves displacement of divalent cations from their binding sites on cell wall lipopolysaccharides (LPS) and the consequent permeabilization of the outer membrane (37).…”