ABSTRACT
Bacterial infections are known to cause severe health-threatening conditions, including sepsis. All attempts to get this disease under control failed in the past, and especially in times of increasing antibiotic resistance, this leads to one of the most urgent medical challenges of our times. We designed a peptide to bind with high affinity to endotoxins, one of the most potent pathogenicity factors involved in triggering sepsis. The peptide Pep19-2.5 reveals high endotoxin neutralization efficiency in vitro, and here, we demonstrate its antiseptic/anti-inflammatory effects in vivo in the mouse models of endotoxemia, bacteremia, and cecal ligation and puncture, as well as in an ex vivo model of human tissue. Furthermore, we show that Pep19-2.5 can bind and neutralize not only endotoxins but also other bacterial pathogenicity factors, such as those from the Gram-positive bacterium Staphylococcus aureus. This broad neutralization efficiency and the additive action of the peptide with common antibiotics makes it an exceptionally appropriate drug candidate against bacterial sepsis and also offers multiple other medication opportunities.
Subject(s)
Lipopolysaccharides/antagonists & inhibitors , Peptides/pharmacology , Staphylococcus aureus/drug effects , Staphylococcus aureus/pathogenicity , Virulence Factors/antagonists & inhibitors , Amino Acid Sequence , Animals , Anti-Bacterial Agents/pharmacology , Bacteremia/drug therapy , Bacteremia/metabolism , Bacteremia/microbiology , Bacteremia/mortality , Disease Models, Animal , Drug Synergism , Endotoxemia/drug therapy , Endotoxemia/metabolism , Endotoxemia/microbiology , Endotoxemia/mortality , Female , Humans , Lipopolysaccharides/biosynthesis , Mice , Mice, Inbred BALB C , Molecular Sequence Data , Peptides/chemical synthesis , Sepsis/drug therapy , Sepsis/metabolism , Sepsis/microbiology , Sepsis/mortality , Staphylococcal Infections/drug therapy , Staphylococcal Infections/metabolism , Staphylococcal Infections/microbiology , Staphylococcal Infections/mortality , Staphylococcus aureus/growth & development , Survival Analysis , Virulence Factors/biosynthesisABSTRACT
The bacterial cell wall represents the primary target for antimicrobial agents. Microbial destruction is accompanied by the release of potent immunostimulatory membrane constituents. Both Gram-positive and Gram-negative bacteria release a variety of lipoproteins and peptidoglycan fragments. Gram-positive bacteria additionally provide lipoteichoic acids, whereas Gram-negative bacteria also release lipopolysaccharide (LPS, endotoxin), essential component of the outer leaflet of the bacterial cell wall and one of the most potent immunostimulatory molecules known. Immune activation therefore can be considered as an adverse effect of antimicrobial destruction and killing during anti-infective treatment. In contrast to antibiotics, the use of cationic amphiphilic antimicrobial peptides allows both effective bacterial killing and inhibition of the immunostimulatory effect of the released bacterial membrane constituents. The administration of antimicrobial peptides alone or in combination with antibiotic agents thus represents a novel strategy in the antiinfective treatment with potentially important beneficial aspects. Here, data are presented which describe immunological and clinical aspects of the use of antimicrobial peptides (AMPs) as therapeutic agents to treat bacterial infection and neutralize the immunostimulatory activity of released cell wall constituents.
