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Abstract
BackgroundUnderstanding how pathogens respond to antimicrobial peptides, and how this compares to currently available antibiotics, is crucial for optimizing antimicrobial therapy. Staphylococcus aureus has several known resistance mechanisms against human cationic antimicrobial peptides (CAMPs). Gene expression changes in S. aureus strain Newman exposed to linear CAMPs were analyzed by DNA microarray. Three antimicrobial peptides were used in the analysis, two are derived from frog, temporin L and dermaseptin K4-S4(1-16), and the ovispirin-1 is obtained from sheep.ResultsThe peptides induced the VraSR cell-wall regulon and several other genes that are also up-regulated in cells treated with vancomycin and other cell wall-active antibiotics. In addition to this similarity, three genes/operons were particularly strongly induced by the peptides: vraDE, SA0205 and SAS016, encoding an ABC transporter, a putative membrane-bound lysostaphin-like peptidase and a small functionally unknown protein, respectively. Ovispirin-1 and dermaseptin K4-S4(1-16), which disrupt lipid bilayers by the carpet mechanism, appeared to be strong inducers of the vraDE operon. We show that high level induction by ovispirin-1 is dependent on the amide modification of the peptide C-terminus. This suggests that the amide group has a crucial role in the activation of the Aps (GraRS) sensory system, the regulator of vraDE. In contrast, temporin L, which disrupts lipid bilayers by forming pores, revealed a weaker inducer of vraDE despite the C-terminal amide modification. Sensitivity testing with CAMPs and other antimicrobials suggested that VraDE is a transporter dedicated to resist bacitracin. We also showed that SA0205 belongs to the VraSR regulon. Furthermore, VraSR was shown to be important for resistance against a wide range of cell wall-active antibiotics and other antimicrobial agents including the amide-modified ovispirin-1, bacitracin, teicoplanin, cefotaxime and 10 other β-lactam antibiotics, chlorpromazine, thioridazine and EGTA.ConclusionDefense against different CAMPs involves not only general signaling pathways but also CAMP-specific ones. These results suggest that CAMPs or a mixture of CAMPs could constitute a potential additive to standard antibiotic treatment.
Highlights
Understanding how pathogens respond to antimicrobial peptides, and how this compares to currently available antibiotics, is crucial for optimizing antimicrobial therapy
The VraSR cell wall regulon, vraDE, SA0205 and SAS016 are strongly induced by cationic antimicrobial peptides Exponentially growing S. aureus cells were treated with Cterminally amidated temporin L, http://www.biomedcentral.com/1471-2164/10/429 ovispirin-1 or dermaseptin K4-S4(116) (dermaseptin K4-S4(1-16)-NH2) at sublethal concentrations which slightly inhibited growth but did not stop it
VraDE is an ABC transporter system dedicated to resist bacitracin, whereas VraSR two-component system affects the resistance against a wider spectrum of antimicrobial agents Our experiments showed that the VraDE ABC transporter and the VraSR two-component system are two CAMPinducible systems which could be important for bacterial cells in resisting the harmful effects of cationic antimicrobial peptides (CAMPs) and possibly other antimicrobial agents
Summary
Understanding how pathogens respond to antimicrobial peptides, and how this compares to currently available antibiotics, is crucial for optimizing antimicrobial therapy. CAMPs contribute to the host defense of microbial invasion on epithelial surfaces by killing engulfed microorganisms in phagocytic cells or modulating inflammatory responses in infections [1,2,3]. These ancient weapons of host defense are typically amphipathic peptides with a net positive charge at physiological pH and they share well-defined α-helical or β-sheet secondary structures. Membrane damage is not the only mechanism whereby CAMPs cause cell death They may affect functions of several other cell components and act as metabolic inhibitors of cellular processes including biosynthesis of the cell wall, nucleic-acids and proteins [1,3]. The cell death can be the result of multiple inhibitory effects
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