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

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Serval ID
serval:BIB_E88D083EA7B3
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Living with an imperfect cell wall: compensation of femAB inactivation in Staphylococcus aureus.
Journal
BMC Genomics
Author(s)
Hübscher J., Jansen A., Kotte O., Schäfer J., Majcherczyk P.A., Harris L.G., Bierbaum G., Heinemann M., Berger-Bächi B.
ISSN
1471-2164[electronic], 1471-2164[linking]
Publication state
Published
Issued date
2007
Volume
8
Pages
307
Language
english
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 beta-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.
Keywords
Bacterial Proteins/genetics, Bacterial Proteins/metabolism, Cell Wall/chemistry, Computational Biology, Gene Silencing, Genes, Bacterial, Genetic Complementation Test, Mutation, Oligonucleotide Array Sequence Analysis, Operon, Polysaccharides/chemistry, Staphylococcus aureus/genetics, Staphylococcus aureus/metabolism, Temperature, Transcription, Genetic
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 13:54
Last modification date
20/08/2019 16:11
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