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

Guillermo      Martinez de Tejada; Susana      Sanchez-Gomez; Iosu      Razquin-Olazaran; Ina      Kowalski; Yani      Kaconis; Lena      Heinbockel; Jorg      Andra; Tobias      Schurholz; Mathias      Hornef; Aline      Dupont; Patrick      Garidel; Karl      Lohner; Thomas      Gutsmann; Sunil      A. David; Klaus      Brandenburg

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 exists 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.

Keywords: Antimicrobial peptides, endotoxin shock, lipopolyamines, lipopolysaccharides, tumor-necrosis-factorα, Gram-negative bacteria, Gram-positive bacteria, septic shock, amphiphilic components, lipoteichoic acids