Open Access Highly Accessed Research article

Living with an imperfect cell wall: compensation of femAB inactivation in Staphylococcus aureus

Judith Hübscher1, Andrea Jansen2, Oliver Kotte3, Juliane Schäfer4, Paul A Majcherczyk5, Llinos G Harris67, Gabriele Bierbaum2, Matthias Heinemann3 and Brigitte Berger-Bächi1*

Author Affiliations

1 Institute of Medical Microbiology, University of Zürich, Zürich, Switzerland

2 Institute for Medical Microbiology, Immunology and Parasitology, University of Bonn, Bonn, Germany

3 Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland

4 Seminar for Statistics, ETH Zürich, Zürich, Switzerland

5 Division of Infectious Diseases, Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

6 AO Research Institute, Davos, Switzerland

7 School of Medicine, University of Wales Swansea, Swansea, UK

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BMC Genomics 2007, 8:307  doi:10.1186/1471-2164-8-307

Published: 4 September 2007

Abstract

Background

Synthesis of the Staphylococcus aureus peptidoglycan pentaglycine interpeptide bridge is catalyzed by the nonribosomal peptidyl transferases FemX, FemA and FemB. Inactivation of the femAB operon reduces the interpeptide to a monoglycine, leading to a poorly crosslinked peptidoglycan. femAB mutants show a reduced growth rate and are hypersusceptible to virtually all antibiotics, including methicillin, making FemAB a potential target to restore β-lactam susceptibility in methicillin-resistant S. aureus (MRSA). Cis-complementation with wild type femAB only restores synthesis of the pentaglycine interpeptide and methicillin resistance, but the growth rate remains low. This study characterizes the adaptations that ensured survival of the cells after femAB inactivation.

Results

In addition to slow growth, the cis-complemented femAB mutant showed temperature sensitivity and a higher methicillin resistance than the wild type. Transcriptional profiling paired with reporter metabolite analysis revealed multiple changes in the global transcriptome. A number of transporters for sugars, glycerol, and glycine betaine, some of which could serve as osmoprotectants, were upregulated. Striking differences were found in the transcription of several genes involved in nitrogen metabolism and the arginine-deiminase pathway, an alternative for ATP production. In addition, microarray data indicated enhanced expression of virulence factors that correlated with premature expression of the global regulators sae, sarA, and agr.

Conclusion

Survival under conditions preventing normal cell wall formation triggered complex adaptations that incurred a fitness cost, showing the remarkable flexibility of S. aureus to circumvent cell wall damage. Potential FemAB inhibitors would have to be used in combination with other antibiotics to prevent selection of resistant survivors.