Population Genomics of Reduced Vancomycin Susceptibility in <named-content content-type="genus-species">Staphylococcus aureus</named-content>

ABSTRACT The increased prevalence of vancomycin-intermediate Staphylococcus aureus (VISA) is an emerging health care threat. Genome-based comparative methods hold great promise to uncover the genetic basis of the VISA phenotype, which remains obscure. S. aureus isolates were collected from a single...

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Autores principales:	Lavanya Rishishwar, Colleen S. Kraft, I. King Jordan
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Staphylococcus aureus antibiotic resistance genomics population genetics vancomycin Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1e895eef3c1443a89c2301092b748e9d
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spelling	oai:doaj.org-article:1e895eef3c1443a89c2301092b748e9d2021-11-15T15:21:14ZPopulation Genomics of Reduced Vancomycin Susceptibility in <named-content content-type="genus-species">Staphylococcus aureus</named-content>10.1128/mSphere.00094-162379-5042https://doaj.org/article/1e895eef3c1443a89c2301092b748e9d2016-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00094-16https://doaj.org/toc/2379-5042ABSTRACT The increased prevalence of vancomycin-intermediate Staphylococcus aureus (VISA) is an emerging health care threat. Genome-based comparative methods hold great promise to uncover the genetic basis of the VISA phenotype, which remains obscure. S. aureus isolates were collected from a single individual that presented with recurrent staphylococcal bacteremia at three time points, and the isolates showed successively reduced levels of vancomycin susceptibility. A population genomic approach was taken to compare patient S. aureus isolates with decreasing vancomycin susceptibility across the three time points. To do this, patient isolates were sequenced to high coverage (~500×), and sequence reads were used to model site-specific allelic variation within and between isolate populations. Population genetic methods were then applied to evaluate the overall levels of variation across the three time points and to identify individual variants that show anomalous levels of allelic change between populations. A successive reduction in the overall levels of population genomic variation was observed across the three time points, consistent with a population bottleneck resulting from antibiotic treatment. Despite this overall reduction in variation, a number of individual mutations were swept to high frequency in the VISA population. These mutations were implicated as potentially involved in the VISA phenotype and interrogated with respect to their functional roles. This approach allowed us to identify a number of mutations previously implicated in VISA along with allelic changes within a novel class of genes, encoding LPXTG motif-containing cell-wall-anchoring proteins, which shed light on a novel mechanistic aspect of vancomycin resistance. IMPORTANCE The emergence and spread of antibiotic resistance among bacterial pathogens are two of the gravest threats to public health facing the world today. We report the development and application of a novel population genomic technique aimed at uncovering the evolutionary dynamics and genetic determinants of antibiotic resistance in Staphylococcus aureus. This method was applied to S. aureus cultures isolated from a single patient who showed decreased susceptibility to the vancomycin antibiotic over time. Our approach relies on the increased resolution afforded by next-generation genome-sequencing technology, and it allowed us to discover a number of S. aureus mutations, in both known and novel gene targets, which appear to have evolved under adaptive pressure to evade vancomycin mechanisms of action. The approach we lay out in this work can be applied to resistance to any number of antibiotics across numerous species of bacterial pathogens.Lavanya RishishwarColleen S. KraftI. King JordanAmerican Society for MicrobiologyarticleStaphylococcus aureusantibiotic resistancegenomicspopulation geneticsvancomycinMicrobiologyQR1-502ENmSphere, Vol 1, Iss 4 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Staphylococcus aureus antibiotic resistance genomics population genetics vancomycin Microbiology QR1-502
spellingShingle	Staphylococcus aureus antibiotic resistance genomics population genetics vancomycin Microbiology QR1-502 Lavanya Rishishwar Colleen S. Kraft I. King Jordan Population Genomics of Reduced Vancomycin Susceptibility in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
description	ABSTRACT The increased prevalence of vancomycin-intermediate Staphylococcus aureus (VISA) is an emerging health care threat. Genome-based comparative methods hold great promise to uncover the genetic basis of the VISA phenotype, which remains obscure. S. aureus isolates were collected from a single individual that presented with recurrent staphylococcal bacteremia at three time points, and the isolates showed successively reduced levels of vancomycin susceptibility. A population genomic approach was taken to compare patient S. aureus isolates with decreasing vancomycin susceptibility across the three time points. To do this, patient isolates were sequenced to high coverage (~500×), and sequence reads were used to model site-specific allelic variation within and between isolate populations. Population genetic methods were then applied to evaluate the overall levels of variation across the three time points and to identify individual variants that show anomalous levels of allelic change between populations. A successive reduction in the overall levels of population genomic variation was observed across the three time points, consistent with a population bottleneck resulting from antibiotic treatment. Despite this overall reduction in variation, a number of individual mutations were swept to high frequency in the VISA population. These mutations were implicated as potentially involved in the VISA phenotype and interrogated with respect to their functional roles. This approach allowed us to identify a number of mutations previously implicated in VISA along with allelic changes within a novel class of genes, encoding LPXTG motif-containing cell-wall-anchoring proteins, which shed light on a novel mechanistic aspect of vancomycin resistance. IMPORTANCE The emergence and spread of antibiotic resistance among bacterial pathogens are two of the gravest threats to public health facing the world today. We report the development and application of a novel population genomic technique aimed at uncovering the evolutionary dynamics and genetic determinants of antibiotic resistance in Staphylococcus aureus. This method was applied to S. aureus cultures isolated from a single patient who showed decreased susceptibility to the vancomycin antibiotic over time. Our approach relies on the increased resolution afforded by next-generation genome-sequencing technology, and it allowed us to discover a number of S. aureus mutations, in both known and novel gene targets, which appear to have evolved under adaptive pressure to evade vancomycin mechanisms of action. The approach we lay out in this work can be applied to resistance to any number of antibiotics across numerous species of bacterial pathogens.
format	article
author	Lavanya Rishishwar Colleen S. Kraft I. King Jordan
author_facet	Lavanya Rishishwar Colleen S. Kraft I. King Jordan
author_sort	Lavanya Rishishwar
title	Population Genomics of Reduced Vancomycin Susceptibility in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_short	Population Genomics of Reduced Vancomycin Susceptibility in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_full	Population Genomics of Reduced Vancomycin Susceptibility in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_fullStr	Population Genomics of Reduced Vancomycin Susceptibility in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_full_unstemmed	Population Genomics of Reduced Vancomycin Susceptibility in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_sort	population genomics of reduced vancomycin susceptibility in <named-content content-type="genus-species">staphylococcus aureus</named-content>
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/1e895eef3c1443a89c2301092b748e9d
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Population Genomics of Reduced Vancomycin Susceptibility in <named-content content-type="genus-species">Staphylococcus aureus</named-content>

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