Whole genome sequencing and complete genetic analysis reveals novel pathways to glycopeptide resistance in Staphylococcus aureus
| Autor: | Ambre Jousselin, Pierre Vaudaux, Adriana Renzoni, Antoinette Monod, Christine Barras, Diego O. Andrey, William L. Kelley, Daniel Pablo Lew |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Staphylococcus aureus
Drug Resistance Microbial/genetics Science Nonsense mutation Microbial Sensitivity Tests Biology medicine.disease_cause Microbiology Deep sequencing Anti-Bacterial Agents/pharmacology 03 medical and health sciences medicine 030304 developmental biology Staphylococci ddc:616 Whole genome sequencing Genetics 0303 health sciences Gram Positive Multidisciplinary 030306 microbiology Teicoplanin Point mutation Histidine kinase Glycopeptides Drug Resistance Microbial Genome Bacterial/genetics Glycopeptide Anti-Bacterial Agents Bacterial Pathogens Medical Microbiology Medicine Staphylococcus aureus/drug effects/genetics Genome Bacterial Glycopeptides/pharmacology medicine.drug Research Article |
| Zdroj: | PLoS ONE, Vol 6, Iss 6, p e21577 (2011) PloS one PLoS ONE PLOS ONE, Vol. 6, No 6 (2011) P. e21577 PloS One |
| ISSN: | 1932-6203 |
| Popis: | The precise mechanisms leading to the emergence of low-level glycopeptide resistance in Staphylococcus aureus are poorly understood. In this study, we used whole genome deep sequencing to detect differences between two isogenic strains: a parental strain and a stable derivative selected stepwise for survival on 4 µg/ml teicoplanin, but which grows at higher drug concentrations (MIC 8 µg/ml). We uncovered only three single nucleotide changes in the selected strain. Nonsense mutations occurred in stp1, encoding a serine/threonine phosphatase, and in yjbH, encoding a post-transcriptional negative regulator of the redox/thiol stress sensor and global transcriptional regulator, Spx. A missense mutation (G45R) occurred in the histidine kinase sensor of cell wall stress, VraS. Using genetic methods, all single, pairwise combinations, and a fully reconstructed triple mutant were evaluated for their contribution to low-level glycopeptide resistance. We found a synergistic cooperation between dual phospho-signalling systems and a subtle contribution from YjbH, suggesting the activation of oxidative stress defences via Spx. To our knowledge, this is the first genetic demonstration of multiple sensor and stress pathways contributing simultaneously to glycopeptide resistance development. The multifactorial nature of glycopeptide resistance in this strain suggests a complex reprogramming of cell physiology to survive in the face of drug challenge. |
| Databáze: | OpenAIRE |
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