Mutation in elongation factor G confers resistance to the antibiotic argyrin in the opportunistic pathogen Pseudomonas aeruginosa.

Piotr Bielecki, Peer Lukat, Kristina Hüsecken, Andreas Dötsch, Heinrich Steinmetz, Rolf W Hartmann, Rolf Müller, Susanne Häussler

Department of Molecular Bacteriology, Helmholtz Center for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.

Chembiochem : a European journal of chemical biology 2012 Nov 5

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The natural myxobacterial product argyrin is a cyclic peptide exhibiting immunosuppressive activity as well as antibacterial activity directed against the highly intrinsically resistant opportunistic pathogen Pseudomonas aeruginosa. In this study, we used whole-genome sequencing technology as a powerful tool to determine the mode of action of argyrin. Sequencing of argyrin-resistant P. aeruginosa isolates selected in vitro uncovered six point mutations that distinguished the resistant mutants from their susceptible parental strain. All six mutations were localized within one gene: fusA1, which encodes for the elongation factor EF-G. After the reintroduction of selected mutations into the susceptible wild type, the strain became resistant to argyrin. Surface plasmon resonance experiments confirmed the interaction of argyrin A with FusA1. Interestingly, EF-G has been previously shown to be the target of the anti-Staphylococcus antibiotic fusidic acid. Mapping of the mutations onto a structural model of EF-G revealed that the mutations conveying resistance against argyrin were clustered within domain III on the side opposite to that involved in fusidic acid binding, thus indicating that argyrin exhibits a new mode of protein synthesis inhibition. Although no mutations causing argyrin resistance have been found in other genes of P. aeruginosa, analysis of the sequence identity in EF-G and its correlation with argyrin resistance in different bacteria imply that additional factors such as uptake of argyrin play a role in the argyrin resistance of other organisms. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Citation

Piotr Bielecki, Peer Lukat, Kristina Hüsecken, Andreas Dötsch, Heinrich Steinmetz, Rolf W Hartmann, Rolf Müller, Susanne Häussler. Mutation in elongation factor G confers resistance to the antibiotic argyrin in the opportunistic pathogen Pseudomonas aeruginosa. Chembiochem : a European journal of chemical biology. 2012 Nov 5;13(16):2339-45