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.
Highlights
Host defense peptides (HDPs) are important effector molecules of the ancient, non-specific innate immune system displaying multiple functions involved in microbial clearance
The two θ-defensins, RTD-1 and RTD-2 (Figure 1), were initially tested for their activities against different staphylococcal species in a standard broth microdilution assay. Both peptides exhibited potent antimicrobial activity and inhibited growth of the three strains tested at concentrations ranging from 0.5 to 6 μg/mL (Table 1)
As θ-defensins and Pep5 both interact with membrane-bound lipoteichoic acid, we investigated whether this interaction facilitates the pore-formation process
Summary
Host defense peptides (HDPs) are important effector molecules of the ancient, non-specific innate immune system displaying multiple functions involved in microbial clearance They may be constitutively expressed or be induced in response to infection or injury, e.g., through activation of Toll-like receptors or pro-inflammatory cytokines. One conserved group of HDPs comprises defensins sensu stricto, which were first discovered in mammals and subsequently found in invertebrates, plants and fungi These peptides are characterized by a disulfide-stabilized β-sheet structure and primarily expressed in epithelial tissues or phagocytic cells [9,10]. They are further divided into three groups, α-, β- and θ-defensins, based on their gene structure as well as spacing and pairing of their six conserved cysteine residues. RTDs do not interfere with peptidoglycan biosynthesis, but rather induce bacterial lysis in staphylococci by interaction with the bacterial membrane and/or release of autolytic enzymes similar to the lantibiotic Pep
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