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Intermediate-type vancomycin resistance (VISA) in genetically-distinct Staphylococcus aureus isolates is linked to specific, reversible metabolic alterations.

Alexander EL, Gardete S, Bar HY, Wells MT, Tomasz A, Rhee KY - PLoS ONE (2014)

Bottom Line: In both series (the first belonging to MRSA clone ST8-USA300, and the second to ST5-USA100), resistance was conferred by a single mutation in yvqF (a negative regulator of the vraSR two-component system associated with vancomycin resistance).In the USA300 series, resistance was reversed by a secondary mutation in vraSR.In this study, we combined systems-level metabolomic profiling with statistical modeling techniques to discover specific, reversible metabolic alterations associated with the VISA phenotype.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America.

ABSTRACT
Intermediate (VISA-type) vancomycin resistance in Staphylococcus aureus has been associated with a range of physiologic and genetic alterations. Previous work described the emergence of VISA-type resistance in two clonally-distinct series of isolates. In both series (the first belonging to MRSA clone ST8-USA300, and the second to ST5-USA100), resistance was conferred by a single mutation in yvqF (a negative regulator of the vraSR two-component system associated with vancomycin resistance). In the USA300 series, resistance was reversed by a secondary mutation in vraSR. In this study, we combined systems-level metabolomic profiling with statistical modeling techniques to discover specific, reversible metabolic alterations associated with the VISA phenotype.

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Heat Map of Altered Metabolites in the VISA, SG-R, Versus its Parent VSSA, SG-R and the revertant VSSA, SG-rev.Heat map displaying the 12 metabolites whose abundance was significantly altered in the VISA isolate, SG-R compared against the parent VSSA, SG-S. Changes in abundance are indicated by color coding with red indicative of increases in mean intracellular abundance relative to the baseline (defined by the abundance in SG-S) and blue indicative of decreases in intracellular abundance on a log (2) scale. Specific p-values for the comparison of SG-R versus SG-S are denoted to the near right of the heat map. Metabolites are grouped according to pathway, denoted to the far right of each metabolite. Metabolites 1–7 reversed directionality in the revertant isolate (SG-rev) indicating a link to vancomycin resistance. Metabolites 8–12, however, did not reverse in SG-rev and are separated by a row to denote this difference. The superscript (a) denotes unable to determine if methylmalate or hydroxyglutarate in the absence of a chemical standard.
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pone-0097137-g004: Heat Map of Altered Metabolites in the VISA, SG-R, Versus its Parent VSSA, SG-R and the revertant VSSA, SG-rev.Heat map displaying the 12 metabolites whose abundance was significantly altered in the VISA isolate, SG-R compared against the parent VSSA, SG-S. Changes in abundance are indicated by color coding with red indicative of increases in mean intracellular abundance relative to the baseline (defined by the abundance in SG-S) and blue indicative of decreases in intracellular abundance on a log (2) scale. Specific p-values for the comparison of SG-R versus SG-S are denoted to the near right of the heat map. Metabolites are grouped according to pathway, denoted to the far right of each metabolite. Metabolites 1–7 reversed directionality in the revertant isolate (SG-rev) indicating a link to vancomycin resistance. Metabolites 8–12, however, did not reverse in SG-rev and are separated by a row to denote this difference. The superscript (a) denotes unable to determine if methylmalate or hydroxyglutarate in the absence of a chemical standard.

Mentions: Specific metabolites whose abundances were altered in JH2 compared against JH1 on hierarchical mixture modeling included intermediates of the urea cycle, purine metabolism, the tri-carboxylic acid (TCA) cycle, glycolysis/gluconeogenesis/pentose phosphate pathway, pyruvate metabolism, and cell wall metabolism, among others (Figure 3). The 12 metabolites whose abundance was significantly altered in the SG series by hierarchical mixture modeling also included intermediates of the urea cycle, TCA cycle, glycolysis/gluconeogenesis/pentose phosphate pathway and pyruvate metabolism, of which seven subsequently reversed in the direction of the parental isolate (albeit sometimes imperfectly) in the revertant, SG-rev (Figure 4).


Intermediate-type vancomycin resistance (VISA) in genetically-distinct Staphylococcus aureus isolates is linked to specific, reversible metabolic alterations.

Alexander EL, Gardete S, Bar HY, Wells MT, Tomasz A, Rhee KY - PLoS ONE (2014)

Heat Map of Altered Metabolites in the VISA, SG-R, Versus its Parent VSSA, SG-R and the revertant VSSA, SG-rev.Heat map displaying the 12 metabolites whose abundance was significantly altered in the VISA isolate, SG-R compared against the parent VSSA, SG-S. Changes in abundance are indicated by color coding with red indicative of increases in mean intracellular abundance relative to the baseline (defined by the abundance in SG-S) and blue indicative of decreases in intracellular abundance on a log (2) scale. Specific p-values for the comparison of SG-R versus SG-S are denoted to the near right of the heat map. Metabolites are grouped according to pathway, denoted to the far right of each metabolite. Metabolites 1–7 reversed directionality in the revertant isolate (SG-rev) indicating a link to vancomycin resistance. Metabolites 8–12, however, did not reverse in SG-rev and are separated by a row to denote this difference. The superscript (a) denotes unable to determine if methylmalate or hydroxyglutarate in the absence of a chemical standard.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016254&req=5

pone-0097137-g004: Heat Map of Altered Metabolites in the VISA, SG-R, Versus its Parent VSSA, SG-R and the revertant VSSA, SG-rev.Heat map displaying the 12 metabolites whose abundance was significantly altered in the VISA isolate, SG-R compared against the parent VSSA, SG-S. Changes in abundance are indicated by color coding with red indicative of increases in mean intracellular abundance relative to the baseline (defined by the abundance in SG-S) and blue indicative of decreases in intracellular abundance on a log (2) scale. Specific p-values for the comparison of SG-R versus SG-S are denoted to the near right of the heat map. Metabolites are grouped according to pathway, denoted to the far right of each metabolite. Metabolites 1–7 reversed directionality in the revertant isolate (SG-rev) indicating a link to vancomycin resistance. Metabolites 8–12, however, did not reverse in SG-rev and are separated by a row to denote this difference. The superscript (a) denotes unable to determine if methylmalate or hydroxyglutarate in the absence of a chemical standard.
Mentions: Specific metabolites whose abundances were altered in JH2 compared against JH1 on hierarchical mixture modeling included intermediates of the urea cycle, purine metabolism, the tri-carboxylic acid (TCA) cycle, glycolysis/gluconeogenesis/pentose phosphate pathway, pyruvate metabolism, and cell wall metabolism, among others (Figure 3). The 12 metabolites whose abundance was significantly altered in the SG series by hierarchical mixture modeling also included intermediates of the urea cycle, TCA cycle, glycolysis/gluconeogenesis/pentose phosphate pathway and pyruvate metabolism, of which seven subsequently reversed in the direction of the parental isolate (albeit sometimes imperfectly) in the revertant, SG-rev (Figure 4).

Bottom Line: In both series (the first belonging to MRSA clone ST8-USA300, and the second to ST5-USA100), resistance was conferred by a single mutation in yvqF (a negative regulator of the vraSR two-component system associated with vancomycin resistance).In the USA300 series, resistance was reversed by a secondary mutation in vraSR.In this study, we combined systems-level metabolomic profiling with statistical modeling techniques to discover specific, reversible metabolic alterations associated with the VISA phenotype.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America.

ABSTRACT
Intermediate (VISA-type) vancomycin resistance in Staphylococcus aureus has been associated with a range of physiologic and genetic alterations. Previous work described the emergence of VISA-type resistance in two clonally-distinct series of isolates. In both series (the first belonging to MRSA clone ST8-USA300, and the second to ST5-USA100), resistance was conferred by a single mutation in yvqF (a negative regulator of the vraSR two-component system associated with vancomycin resistance). In the USA300 series, resistance was reversed by a secondary mutation in vraSR. In this study, we combined systems-level metabolomic profiling with statistical modeling techniques to discover specific, reversible metabolic alterations associated with the VISA phenotype.

Show MeSH
Related in: MedlinePlus