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Title

A de novo-designed antimicrobial peptide with activity against multiresistant Staphylococcus aureus acting on RsbW kinase

Authors
Dangel, Alexandra
Ackermann, Nikolaus
Abdel-Hadi, Omar
Maier, Richard
Onder, Kamil
Müller, Carsten W
Pané-Farré, Jan
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Published in FASEB Journal. 2013, vol. 27, no. 11, p. 4476-88
Abstract Antimicrobial peptides are a promising complement to common antibiotics, development of resistance to which is a growing problem. Here we present a de novo-designed peptide, SP1-1 (RKKRLKLLKRLL-NH2), with antimicrobial activity against multiresistant Staphylococcus aureus (minimal inhibitory concentration: 6.25 μM). Elucidation of the mode of action of this peptide revealed a strong interaction with RsbW kinase (Kd: 6.01±2.73 nM), a serine kinase negatively regulating the activity of the transcription factor σB (SigB). SP1-1 binding and functional modulation of RsbW were shown in vitro by a combination of biochemical, molecular, and biophysical methods, which were further genetically evidenced in vivo by analysis of S. aureus ΔsigB deletion mutants. Intracellular localization of the peptide was demonstrated using nanometer-scaled secondary ion mass spectrometry. Moreover, microarray analysis revealed that transcription of numerous genes, involved in cell wall and amino acid metabolism, transport mechanisms, virulence, and pigmentation, is affected. Interestingly, several WalR binding motif containing genes are induced by SP1-1. In sum, the designed peptide SP1-1 seems to have multiple modes of action, including inhibition of a kinase, and therefore might contribute to the development of new antibacterial compounds, giving bacterial kinase inhibition a closer inspection.-Dangel, A., Ackermann, N., Abdel-Hadi, O., Maier, R., Önder, K., Francois, P., Müller, C. W., Pané-Farré, J., Engelmann, S., Schrenzel, J., Heesemann, J., Lindermayr, C. A de novo-designed antimicrobial peptide with activity against multiresistant Staphylococcus aureus acting on RsbW kinase.
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PMID: 23901070
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Article (Published version) (758 Kb) - public document Free access
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Research group Analyse génomique et fonctionnelle du staphylocoque doré (604)
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DANGEL, Alexandra et al. A de novo-designed antimicrobial peptide with activity against multiresistant Staphylococcus aureus acting on RsbW kinase. In: FASEB Journal, 2013, vol. 27, n° 11, p. 4476-88. https://archive-ouverte.unige.ch/unige:33349

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Deposited on : 2014-01-16

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