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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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Principal component and hierarchical cluster analyses show separation of isolates by resistance phenotype.Principal component analysis (A) of the metabolic profiles of all isolates from both series again shows a separation of isolates by resistance phenotype. Specifically, the metabolic profiles of parent VSSA isolates SG-S (green squares) and JH1 (black dots) form a single cluster (green ellipse), while those corresponding to VISA isolates SG-R (dark blue diamonds) and JH2 (red circles) form two separate clusters (dark blue ellipse and red ellipse, respectively) along the same vector of change (denoted by the black arrow) to the left of the VSSA cluster. The metabolic profiles corresponding to the revertant SG-rev (light blue diamonds) cluster between the susceptible parent (SG-S) and resistant (SG-R) isolates, consistent with its revertant phenotype (light blue ellipse). (B) Results of hierarchical cluster analysis also show that the metabolic profiles of all five isolates from both series separate by resistance phenotype, forming two distinct branches with the VISA isolates JH2 and SG-R on the left and VSSAs SG-S, JH1 and SG-rev on the right, though one replicate of SG-R (SG-R5) was found to cluster with the parental VSSA isolates (red asterix).
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pone-0097137-g002: Principal component and hierarchical cluster analyses show separation of isolates by resistance phenotype.Principal component analysis (A) of the metabolic profiles of all isolates from both series again shows a separation of isolates by resistance phenotype. Specifically, the metabolic profiles of parent VSSA isolates SG-S (green squares) and JH1 (black dots) form a single cluster (green ellipse), while those corresponding to VISA isolates SG-R (dark blue diamonds) and JH2 (red circles) form two separate clusters (dark blue ellipse and red ellipse, respectively) along the same vector of change (denoted by the black arrow) to the left of the VSSA cluster. The metabolic profiles corresponding to the revertant SG-rev (light blue diamonds) cluster between the susceptible parent (SG-S) and resistant (SG-R) isolates, consistent with its revertant phenotype (light blue ellipse). (B) Results of hierarchical cluster analysis also show that the metabolic profiles of all five isolates from both series separate by resistance phenotype, forming two distinct branches with the VISA isolates JH2 and SG-R on the left and VSSAs SG-S, JH1 and SG-rev on the right, though one replicate of SG-R (SG-R5) was found to cluster with the parental VSSA isolates (red asterix).

Mentions: Comparison of the metabolic profiles of isolates SG-S, SG-R and SG-rev by principal component analysis (PCA) of the 72 identified metabolites demonstrated clustering of samples by resistance phenotype (Figure 1A). Specifically, the metabolic profiles of SG-S and SG-R formed separate clusters on PCA, while those of SG-rev clustered between these two groups (Figure 1A), suggesting that some, but not all of the metabolic changes associated with acquisition of vancomycin resistance in SG-R reversed with the loss of resistance in SG-rev. Principal component analysis of the metabolic profiles of the JH isolates showed a similar segregation of samples by resistance phenotype with JH1 and JH2 forming distinct clusters, though one outlier (JH2-sample 10) was noted (Figure 1B). Notably, on principal component analysis of all isolates from both series, we again noted clustering according to resistance phenotype. Specifically, the metabolic profiles of the “parent” vancomycin susceptible isolates, JH1 and SG-S, formed a single cluster (Figure 2A, green ellipse) while those of SG-S and JH-2 formed separate clusters (red and dark blue ellipses, respectively) along the same vector of change (as denoted by the black arrow) from the cluster corresponding to the susceptible isolates. As seen in the principal component analysis of the SG series alone, the metabolic profiles of the SG-rev isolates again clustered between those of its susceptible parent (SG-S) and resistant (SG-R) isolates, overlapping both.


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)

Principal component and hierarchical cluster analyses show separation of isolates by resistance phenotype.Principal component analysis (A) of the metabolic profiles of all isolates from both series again shows a separation of isolates by resistance phenotype. Specifically, the metabolic profiles of parent VSSA isolates SG-S (green squares) and JH1 (black dots) form a single cluster (green ellipse), while those corresponding to VISA isolates SG-R (dark blue diamonds) and JH2 (red circles) form two separate clusters (dark blue ellipse and red ellipse, respectively) along the same vector of change (denoted by the black arrow) to the left of the VSSA cluster. The metabolic profiles corresponding to the revertant SG-rev (light blue diamonds) cluster between the susceptible parent (SG-S) and resistant (SG-R) isolates, consistent with its revertant phenotype (light blue ellipse). (B) Results of hierarchical cluster analysis also show that the metabolic profiles of all five isolates from both series separate by resistance phenotype, forming two distinct branches with the VISA isolates JH2 and SG-R on the left and VSSAs SG-S, JH1 and SG-rev on the right, though one replicate of SG-R (SG-R5) was found to cluster with the parental VSSA isolates (red asterix).
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Related In: Results  -  Collection

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

pone-0097137-g002: Principal component and hierarchical cluster analyses show separation of isolates by resistance phenotype.Principal component analysis (A) of the metabolic profiles of all isolates from both series again shows a separation of isolates by resistance phenotype. Specifically, the metabolic profiles of parent VSSA isolates SG-S (green squares) and JH1 (black dots) form a single cluster (green ellipse), while those corresponding to VISA isolates SG-R (dark blue diamonds) and JH2 (red circles) form two separate clusters (dark blue ellipse and red ellipse, respectively) along the same vector of change (denoted by the black arrow) to the left of the VSSA cluster. The metabolic profiles corresponding to the revertant SG-rev (light blue diamonds) cluster between the susceptible parent (SG-S) and resistant (SG-R) isolates, consistent with its revertant phenotype (light blue ellipse). (B) Results of hierarchical cluster analysis also show that the metabolic profiles of all five isolates from both series separate by resistance phenotype, forming two distinct branches with the VISA isolates JH2 and SG-R on the left and VSSAs SG-S, JH1 and SG-rev on the right, though one replicate of SG-R (SG-R5) was found to cluster with the parental VSSA isolates (red asterix).
Mentions: Comparison of the metabolic profiles of isolates SG-S, SG-R and SG-rev by principal component analysis (PCA) of the 72 identified metabolites demonstrated clustering of samples by resistance phenotype (Figure 1A). Specifically, the metabolic profiles of SG-S and SG-R formed separate clusters on PCA, while those of SG-rev clustered between these two groups (Figure 1A), suggesting that some, but not all of the metabolic changes associated with acquisition of vancomycin resistance in SG-R reversed with the loss of resistance in SG-rev. Principal component analysis of the metabolic profiles of the JH isolates showed a similar segregation of samples by resistance phenotype with JH1 and JH2 forming distinct clusters, though one outlier (JH2-sample 10) was noted (Figure 1B). Notably, on principal component analysis of all isolates from both series, we again noted clustering according to resistance phenotype. Specifically, the metabolic profiles of the “parent” vancomycin susceptible isolates, JH1 and SG-S, formed a single cluster (Figure 2A, green ellipse) while those of SG-S and JH-2 formed separate clusters (red and dark blue ellipses, respectively) along the same vector of change (as denoted by the black arrow) from the cluster corresponding to the susceptible isolates. As seen in the principal component analysis of the SG series alone, the metabolic profiles of the SG-rev isolates again clustered between those of its susceptible parent (SG-S) and resistant (SG-R) isolates, overlapping both.

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