Comprehensive Genomic Investigation of Adaptive Mutations Driving the Low-Level Oxacillin Resistance Phenotype in <named-content content-type="genus-species">Staphylococcus aureus</named-content>

ABSTRACT Antistaphylococcal penicillins such as oxacillin are the key antibiotics in the treatment of invasive methicillin-susceptible Staphylococcus aureus (MSSA) infections; however, mec gene-independent resistance adaptation can cause treatment failure. Despite its clinical relevance, the basis o...

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Autores principales:	Stefano G. Giulieri, Romain Guérillot, Jason C. Kwong, Ian R. Monk, Ashleigh S. Hayes, Diane Daniel, Sarah Baines, Norelle L. Sherry, Natasha E. Holmes, Peter Ward, Wei Gao, Torsten Seemann, Timothy P. Stinear, Benjamin P. Howden
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Staphylococcus aureus antibiotic resistance β-lactams genomics Microbiology QR1-502
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spelling	oai:doaj.org-article:16e4fb535fb74b31acb798bc483a9ccc2021-11-15T15:55:44ZComprehensive Genomic Investigation of Adaptive Mutations Driving the Low-Level Oxacillin Resistance Phenotype in <named-content content-type="genus-species">Staphylococcus aureus</named-content>10.1128/mBio.02882-202150-7511https://doaj.org/article/16e4fb535fb74b31acb798bc483a9ccc2020-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02882-20https://doaj.org/toc/2150-7511ABSTRACT Antistaphylococcal penicillins such as oxacillin are the key antibiotics in the treatment of invasive methicillin-susceptible Staphylococcus aureus (MSSA) infections; however, mec gene-independent resistance adaptation can cause treatment failure. Despite its clinical relevance, the basis of this phenomenon remains poorly understood. Here, we investigated the genomic adaptation to oxacillin at an unprecedented scale using a large collection of 503 clinical mec-negative isolates and 30 in vitro-adapted isolates from independent oxacillin exposures. By combining comparative genomics, evolutionary convergence, and genome-wide association analysis, we found 21 genetic loci associated with low-level oxacillin resistance, underscoring the polygenic nature of this phenotype. Evidence of adaptation was particularly strong for the c-di-AMP signal transduction pathways (gdpP and dacA) and in the clpXP chaperone-protease complex. The role of mutations in gdpP in conferring low-level oxacillin resistance was confirmed by allele-swapping experiments. We found that resistance to oxacillin emerges at high frequency in vitro (median, 2.9 × 10−6; interquartile range [IQR], 1.9 × 10−6 to 3.9 × 10−6), which is consistent with a recurrent minimum inhibitory concentration (MIC) increase across the global phylogeny of clinical isolates. Nevertheless, adaptation in clinical isolates appears sporadically, with no stably adapted lineages, suggesting a high fitness cost of resistance, confirmed by growth assessment of mutants in rich media. Our data provide a broader understanding of the emergence and dynamics of oxacillin resistance adaptation in S. aureus and a framework for future surveillance of this clinically important phenomenon. IMPORTANCE The majority of Staphylococcus aureus strains causing human disease are methicillin-susceptible (MSSA) and can be treated with antistaphylococcal penicillins (such as oxacillin). While acquisition of the mec gene represents the main resistance mechanism to oxacillin, S. aureus can acquire low-level resistance through adaptive mutations in other genes. In this study, we used genomic approaches to understand the basis of S. aureus adaption to oxacillin and its dynamic at the population level. By combining a genome analysis of clinical isolates from persistent MSSA infections, in vitro selection of oxacillin resistance, and genome-wide association analysis on a large collection of isolates, we identified 21 genes linked to secondary oxacillin resistance. Adaptive mutations in these genes were easy to select when S. aureus was exposed to oxacillin, but they also came at a substantial cost in terms of bacterial fitness, suggesting that this phenotype emerges preferentially in the setting of sustained antibiotic exposure.Stefano G. GiulieriRomain GuérillotJason C. KwongIan R. MonkAshleigh S. HayesDiane DanielSarah BainesNorelle L. SherryNatasha E. HolmesPeter WardWei GaoTorsten SeemannTimothy P. StinearBenjamin P. HowdenAmerican Society for MicrobiologyarticleStaphylococcus aureusantibiotic resistanceβ-lactamsgenomicsMicrobiologyQR1-502ENmBio, Vol 11, Iss 6 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Staphylococcus aureus antibiotic resistance β-lactams genomics Microbiology QR1-502
spellingShingle	Staphylococcus aureus antibiotic resistance β-lactams genomics Microbiology QR1-502 Stefano G. Giulieri Romain Guérillot Jason C. Kwong Ian R. Monk Ashleigh S. Hayes Diane Daniel Sarah Baines Norelle L. Sherry Natasha E. Holmes Peter Ward Wei Gao Torsten Seemann Timothy P. Stinear Benjamin P. Howden Comprehensive Genomic Investigation of Adaptive Mutations Driving the Low-Level Oxacillin Resistance Phenotype in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
description	ABSTRACT Antistaphylococcal penicillins such as oxacillin are the key antibiotics in the treatment of invasive methicillin-susceptible Staphylococcus aureus (MSSA) infections; however, mec gene-independent resistance adaptation can cause treatment failure. Despite its clinical relevance, the basis of this phenomenon remains poorly understood. Here, we investigated the genomic adaptation to oxacillin at an unprecedented scale using a large collection of 503 clinical mec-negative isolates and 30 in vitro-adapted isolates from independent oxacillin exposures. By combining comparative genomics, evolutionary convergence, and genome-wide association analysis, we found 21 genetic loci associated with low-level oxacillin resistance, underscoring the polygenic nature of this phenotype. Evidence of adaptation was particularly strong for the c-di-AMP signal transduction pathways (gdpP and dacA) and in the clpXP chaperone-protease complex. The role of mutations in gdpP in conferring low-level oxacillin resistance was confirmed by allele-swapping experiments. We found that resistance to oxacillin emerges at high frequency in vitro (median, 2.9 × 10−6; interquartile range [IQR], 1.9 × 10−6 to 3.9 × 10−6), which is consistent with a recurrent minimum inhibitory concentration (MIC) increase across the global phylogeny of clinical isolates. Nevertheless, adaptation in clinical isolates appears sporadically, with no stably adapted lineages, suggesting a high fitness cost of resistance, confirmed by growth assessment of mutants in rich media. Our data provide a broader understanding of the emergence and dynamics of oxacillin resistance adaptation in S. aureus and a framework for future surveillance of this clinically important phenomenon. IMPORTANCE The majority of Staphylococcus aureus strains causing human disease are methicillin-susceptible (MSSA) and can be treated with antistaphylococcal penicillins (such as oxacillin). While acquisition of the mec gene represents the main resistance mechanism to oxacillin, S. aureus can acquire low-level resistance through adaptive mutations in other genes. In this study, we used genomic approaches to understand the basis of S. aureus adaption to oxacillin and its dynamic at the population level. By combining a genome analysis of clinical isolates from persistent MSSA infections, in vitro selection of oxacillin resistance, and genome-wide association analysis on a large collection of isolates, we identified 21 genes linked to secondary oxacillin resistance. Adaptive mutations in these genes were easy to select when S. aureus was exposed to oxacillin, but they also came at a substantial cost in terms of bacterial fitness, suggesting that this phenotype emerges preferentially in the setting of sustained antibiotic exposure.
format	article
author	Stefano G. Giulieri Romain Guérillot Jason C. Kwong Ian R. Monk Ashleigh S. Hayes Diane Daniel Sarah Baines Norelle L. Sherry Natasha E. Holmes Peter Ward Wei Gao Torsten Seemann Timothy P. Stinear Benjamin P. Howden
author_facet	Stefano G. Giulieri Romain Guérillot Jason C. Kwong Ian R. Monk Ashleigh S. Hayes Diane Daniel Sarah Baines Norelle L. Sherry Natasha E. Holmes Peter Ward Wei Gao Torsten Seemann Timothy P. Stinear Benjamin P. Howden
author_sort	Stefano G. Giulieri
title	Comprehensive Genomic Investigation of Adaptive Mutations Driving the Low-Level Oxacillin Resistance Phenotype in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_short	Comprehensive Genomic Investigation of Adaptive Mutations Driving the Low-Level Oxacillin Resistance Phenotype in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_full	Comprehensive Genomic Investigation of Adaptive Mutations Driving the Low-Level Oxacillin Resistance Phenotype in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_fullStr	Comprehensive Genomic Investigation of Adaptive Mutations Driving the Low-Level Oxacillin Resistance Phenotype in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_full_unstemmed	Comprehensive Genomic Investigation of Adaptive Mutations Driving the Low-Level Oxacillin Resistance Phenotype in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_sort	comprehensive genomic investigation of adaptive mutations driving the low-level oxacillin resistance phenotype in <named-content content-type="genus-species">staphylococcus aureus</named-content>
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/16e4fb535fb74b31acb798bc483a9ccc
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Comprehensive Genomic Investigation of Adaptive Mutations Driving the Low-Level Oxacillin Resistance Phenotype in <named-content content-type="genus-species">Staphylococcus aureus</named-content>

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