Killing of Staphylococci by θ-Defensins Involves Membrane Impairment and Activation of Autolytic Enzymes

Abstract

θ-Defensins are cyclic antimicrobial peptides expressed in leukocytes of Old world monkeys. To get insight into their antibacterial mode of action, we studied the activity of RTDs (rhesus macaque θ-defensins) against staphylococci. We found that in contrast to other defensins, RTDs do not interfere with peptidoglycan biosynthesis, but rather induce bacterial lysis in staphylococci by interaction with the bacterial membrane and/or release of cell wall lytic enzymes. Potassium efflux experiments and membrane potential measurements revealed that the membrane impairment by RTDs strongly depends on the energization of the membrane. In addition, RTD treatment caused the release of Atl-derived cell wall lytic enzymes probably by interaction with membrane-bound lipoteichoic acid. Thus, the premature and uncontrolled activity of these enzymes contributes strongly to the overall killing by θ-defensins. Interestingly, a similar mode of action has been described for Pep5, an antimicrobial peptide of bacterial origin.

Rhesus θ-defensin-1 (RTD-1) exhibitsin vitroandin vivoactivity against cystic fibrosis strains ofPseudomonas aeruginosa

“…12 The mechanism of the antibacterial effect of RTD-1 was investigated in studies on S. aureus and E. coli and is attributed to peptide-induced permeabilization/ impairment of the cytoplasmic membrane of both organisms. 11,29 In this study, we evaluated the antibacterial activity of RTD-1 against CF clinical isolates of P. aeruginosa, including isolates with mucoid, MDR and colistin-resistant phenotypes. RTD-1 was bactericidal against a panel of antibiotic-resistant clinical isolates including several strains with phoPQ and/or pmrAB mutations that confer high-level resistance to colistin.…”

More Than a Pore: A Current Perspective on the In Vivo Mode of Action of the Lipopeptide Antibiotic Daptomycin

“…An interesting observation pertaining to autolysis was made for another antibiotic class, the theta-defensins. These peptides trigger autolysis by binding LTAs in S. aureus [117]. In this organism, the major autolysin Atl is controlled by an interplay of WTAs and LTAs.…”

“…WTAs in the old cell wall repel Atl and force it to the division site, where it binds to LTAs and exerts its autolytic activity to selectively lyse the peptidoglycan crosswall between daughter cells [118,119]. Upon binding to LTA, theta-defensins release Atl causing uncontrolled digestion of cell wall peptidoglycan and thus cell lysis [117]. Considering the findings for daptomycin concerning autolysis [101,102] and LTA A similar behavior was observed for human beta-defensin 1, which was shown to display a low affinity to lipid II, probably mainly due to electrostatic interactions of the positively charged peptide with the negatively charged pyrophosphate group.…”

“…WTAs in the old cell wall repel Atl and force it to the division site, where it binds to LTAs and exerts its autolytic activity to selectively lyse the peptidoglycan crosswall between daughter cells [118,119]. Upon binding to LTA, theta-defensins release Atl causing uncontrolled digestion of cell wall peptidoglycan and thus cell lysis [117]. Considering the findings for daptomycin concerning autolysis [101,102] and LTA inhibition [78,79,81,120], it will be interesting to examine whether daptomycin induces autolysis through a similar mechanism.…”

Inhibitory Activity of a Scorpion Defensin BmKDfsin3 against Hepatitis C Virus

“…Many studies have previously reported that defensins have antibacterial, antiviral and ion channel-modulation activities [32][33][34]. Recently, there are many discoveries regarding antiviral defensin polypeptides from scorpions, which may be new candidates for antiviral drug molecules.…”