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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 Metabolites In Which Alterations in Intracellular Abundance was Linked to VISA-type Resistance.Heat map displaying the 7 metabolites whose abundance was significantly altered in the VISA isolates from both series (SG-R and JH2) compared against the parent VSSA isolates (SG-S and JH1) and reversed directionality in the revertant, SG-rev, indicating a link to the vancomycin resistance phenotype. Of these seven metabolites, all but one (aminoadipate) changed in a similar fashion in both VISA isolates compared against the parent VSSA isolates. 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. The superscript (a) denotes unable to determine if methylmalate or hydroxyglutarate in the absence of a chemical standard.
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pone-0097137-g005: Heat Map of Metabolites In Which Alterations in Intracellular Abundance was Linked to VISA-type Resistance.Heat map displaying the 7 metabolites whose abundance was significantly altered in the VISA isolates from both series (SG-R and JH2) compared against the parent VSSA isolates (SG-S and JH1) and reversed directionality in the revertant, SG-rev, indicating a link to the vancomycin resistance phenotype. Of these seven metabolites, all but one (aminoadipate) changed in a similar fashion in both VISA isolates compared against the parent VSSA isolates. 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. The superscript (a) denotes unable to determine if methylmalate or hydroxyglutarate in the absence of a chemical standard.

Mentions: Of the 7 metabolites whose intracellular abundance was significantly altered in both series of isolates on hierarchical mixture modeling, and returned in the directionality of baseline in the revertant, SG-rev (albeit sometimes imperfectly), 6 changed in the same direction in the VISA isolates from both series (SG-R or JH2) when compared against their respective parental VSSA strain (i.e. metabolites 1–2 increased in both VISAs and metabolites 3–6 decreased in both VISAs) (Figure 5). Results of SAM analyses similarly yielded 11 metabolites whose abundance was significantly altered in both VISA isolates and returned in the direction of baseline in the revertant, SG-rev. Of these 11, ten were altered in the same direction in the VISA isolate from both series (Figure S5). All six metabolites which were similarly altered in both VISAs on hierarchical mixture model analyses were also altered on SAM analyses, and included intermediates involved in three metabolic pathways – the urea cycle (aminobutanoate, citrulline) pentose phosphate pathway (pentose phosphate) and the TCA cycle (methylmalate) - among others [20], [21] (Figure 5, Figure S5). As the abundance of these 6 metabolites was significantly altered in a similar manner in the VISA isolate in both series and returned towards levels of the parental isolate in the revertant, they most likely represent the metabolic correlates of yvqF-associated VISA-type resistance.


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 Metabolites In Which Alterations in Intracellular Abundance was Linked to VISA-type Resistance.Heat map displaying the 7 metabolites whose abundance was significantly altered in the VISA isolates from both series (SG-R and JH2) compared against the parent VSSA isolates (SG-S and JH1) and reversed directionality in the revertant, SG-rev, indicating a link to the vancomycin resistance phenotype. Of these seven metabolites, all but one (aminoadipate) changed in a similar fashion in both VISA isolates compared against the parent VSSA isolates. 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. 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-g005: Heat Map of Metabolites In Which Alterations in Intracellular Abundance was Linked to VISA-type Resistance.Heat map displaying the 7 metabolites whose abundance was significantly altered in the VISA isolates from both series (SG-R and JH2) compared against the parent VSSA isolates (SG-S and JH1) and reversed directionality in the revertant, SG-rev, indicating a link to the vancomycin resistance phenotype. Of these seven metabolites, all but one (aminoadipate) changed in a similar fashion in both VISA isolates compared against the parent VSSA isolates. 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. The superscript (a) denotes unable to determine if methylmalate or hydroxyglutarate in the absence of a chemical standard.
Mentions: Of the 7 metabolites whose intracellular abundance was significantly altered in both series of isolates on hierarchical mixture modeling, and returned in the directionality of baseline in the revertant, SG-rev (albeit sometimes imperfectly), 6 changed in the same direction in the VISA isolates from both series (SG-R or JH2) when compared against their respective parental VSSA strain (i.e. metabolites 1–2 increased in both VISAs and metabolites 3–6 decreased in both VISAs) (Figure 5). Results of SAM analyses similarly yielded 11 metabolites whose abundance was significantly altered in both VISA isolates and returned in the direction of baseline in the revertant, SG-rev. Of these 11, ten were altered in the same direction in the VISA isolate from both series (Figure S5). All six metabolites which were similarly altered in both VISAs on hierarchical mixture model analyses were also altered on SAM analyses, and included intermediates involved in three metabolic pathways – the urea cycle (aminobutanoate, citrulline) pentose phosphate pathway (pentose phosphate) and the TCA cycle (methylmalate) - among others [20], [21] (Figure 5, Figure S5). As the abundance of these 6 metabolites was significantly altered in a similar manner in the VISA isolate in both series and returned towards levels of the parental isolate in the revertant, they most likely represent the metabolic correlates of yvqF-associated VISA-type resistance.

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