Kaconis, Y. (Yani)
- Publications
- item.page.relationships.isContributorAdvisorOfPublication
- item.page.relationships.isContributorOfPublication
4 results
Search Results
Now showing 1 - 4 of 4
- The antimicrobial peptide cathelicidin and polymyxin B neutralize endotoxins by a multifactorial mechanism including not only direct LPS-interaction but also targeting of host cell membrane domains(PNAS, 2021) Brandenburg, K. (Klaus); Kopp, F. (Franziska); Kaconis, Y. (Yani); Donoghue, A. (Annemarie); Gutsmann, T. (Thomas); Nehls, C. (Christian); Koistinen, M. (Max); Sánchez-Gómez, S. (Susana); Wernecke, J. (Julia); Sevcsik, E. (Eva); Andrä, J. (Jörg); Martinez-de-Tejada, G. (Guillermo); Schütz, G.J. (Gerhard J.); Paulowski, L. (Laura); Brameshuber, M. (Mario); Lohner, K. (Karl); Keese, S. (Susanne); Garidel, P. (Patrick); Schromm, A.B. (Andra B.)Antimicrobial peptides (AMPs) contribute to an effective protection against infections. The antibacterial function of AMPs depends on their interactions with microbial membranes and lipids, such as lipopolysaccharide (LPS; endotoxin). Hyperinflammation induced by endotoxin is a key factor in bacterial sepsis and many other human diseases. Here, we provide a comprehensive profile of peptide-mediated LPS neutralization by systematic analysis of the effects of a set of AMPs and the peptide antibiotic polymyxin B (PMB) on the physicochemistry of endotoxin, macrophage activation, and lethality in mice. Mechanistic studies revealed that the host defense peptide LL-32 and PMB each reduce LPS-mediated activation also via a direct interaction of the peptides with the host cell. As a biophysical basis, we demonstrate modifications of the structure of cholesterol-rich membrane domains and the association of glycosylphosphatidylinositol (GPI)-anchored proteins. Our discovery of a host cell-directed mechanism of immune control contributes an important aspect in the development and therapeutic use of AMPs.
- Biophysical mechanisms of endotoxin neutralization by cationic amphiphilic peptides(Cell Press (Elsevier), 2011) Howe, J. (Jörg); Brauser, A. (Annemarie); Brandenburg, K. (Klaus); Kowalski, I. (Ina); Kaconis, Y. (Yani); Gutsmann, T. (Thomas); Rossle, M. (Manfred); Martinez-de-Tejada, G. (Guillermo); Razquin-Olazaran, I. (Iosu); Iñigo, M. (Melania); Garidel, P. (Patrick); Richter, W. (Walter)Bacterial endotoxins (lipopolysaccharides (LPS)) are strong elicitors of the human immune system by interacting with serum and membrane proteins such as lipopolysaccharide-binding protein (LBP) and CD14 with high specificity. At LPS concentrations as low as 0.3 ng/ml, such interactions may lead to severe pathophysiological effects, including sepsis and septic shock. One approach to inhibit an uncontrolled inflammatory reaction is the use of appropriate polycationic and amphiphilic antimicrobial peptides, here called synthetic anti-LPS peptides (SALPs). We designed various SALP structures and investigated their ability to inhibit LPS-induced cytokine secretion in vitro, their protective effect in a mouse model of sepsis, and their cytotoxicity in physiological human cells. Using a variety of biophysical techniques, we investigated selected SALPs with considerable differences in their biological responses to characterize and understand the mechanism of LPS inactivation by SALPs. Our investigations show that neutralization of LPS by peptides is associated with a fluidization of the LPS acyl chains, a strong exothermic Coulomb interaction between the two compounds, and a drastic change of the LPS aggregate type from cubic into multilamellar, with an increase in the aggregate sizes, inhibiting the binding of LBP and other mammalian proteins to the endotoxin. At the same time, peptide binding to phospholipids of human origin (e.g., phosphatidylcholine) does not cause essential structural changes, such as changes in membrane fluidity and bilayer structure. The absence of cytotoxicity is explained by the high specificity of the interaction of the peptides with LPS.
- New antiseptic peptides to protect against endotoxin-mediated shock(American Society for Microbiology, 2010) Howe, J. (Jörg); Bartels, R. (Rainer); Brandenburg, K. (Klaus); Kowalski, I. (Ina); Moriyon, I. (Ignacio); Kaconis, Y. (Yani); Gutsmann, T. (Thomas); Sánchez-Gómez, S. (Susana); Rossle, M. (Manfred); Martinez-de-Tejada, G. (Guillermo); Razquin-Olazaran, I. (Iosu); Schürholz, T. (Tobias); Hornef, M. (Mathias)Systemic bacterial infections are associated with high mortality. The access of bacteria or constituents thereof to systemic circulation induces the massive release of immunomodulatory mediators, ultimately causing tissue hypoperfusion and multiple-organ failure despite adequate antibiotic treatment. Lipid A, the "endotoxic principle" of bacterial lipopolysaccharide (LPS), is one of the major bacterial immunostimuli. Here we demonstrate the biological efficacy of rationally designed new synthetic antilipopolysaccharide peptides (SALPs) based on the Limulus anti-LPS factor for systemic application. We show efficient inhibition of LPS-induced cytokine release and protection from lethal septic shock in vivo, whereas cytotoxicity was not observed under physiologically relevant conditions and concentrations. The molecular mechanism of LPS neutralization was elucidated by biophysical techniques. The lipid A part of LPS is converted from its "endotoxic conformation," the cubic aggregate structure, into an inactive multilamellar structure, and the binding affinity of the peptide to LPS exceeds those of known LPS-binding proteins, such as LPS-binding protein (LBP). Our results thus delineate a novel therapeutic strategy for the clinical management of patients with septic shock.
- Bacterial cell wall compounds as promising targets of antimicrobial agents I. Antimicrobial peptides and lipopolyamines(Bentham Science, 2012) Brandenburg, K. (Klaus); Kowalski, I. (Ina); Kaconis, Y. (Yani); Gutsmann, T. (Thomas); Sánchez-Gómez, S. (Susana); David, S.A. (Sunil A.); Andrä, J. (Jörg); Martinez-de-Tejada, G. (Guillermo); Dupont, A. (Aline); Schürholz, T. (Tobias); Garidel, P. (Patrick); Hornef, M. (Mathias)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.