Convergent Evolution Driven by Rifampin Exacerbates the Global Burden of Drug-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content>

ABSTRACT Mutations in the beta-subunit of bacterial RNA polymerase (RpoB) cause resistance to rifampin (Rifr), a critical antibiotic for treatment of multidrug-resistant Staphylococcus aureus. In vitro studies have shown that RpoB mutations confer decreased susceptibility to other antibiotics, but t...

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Autores principales:	Romain Guérillot, Anders Gonçalves da Silva, Ian Monk, Stefano Giulieri, Takehiro Tomita, Eloise Alison, Jessica Porter, Sacha Pidot, Wei Gao, Anton Y. Peleg, Torsten Seemann, Timothy P. Stinear, Benjamin P. Howden
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Staphylococcus aureus adaptive mutations adaptive resistance antibiotic resistance drug resistance evolution genomics Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/dff0eaead17b49d387ed2d1c4aecb738
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spelling	oai:doaj.org-article:dff0eaead17b49d387ed2d1c4aecb7382021-11-15T15:22:01ZConvergent Evolution Driven by Rifampin Exacerbates the Global Burden of Drug-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content>10.1128/mSphere.00550-172379-5042https://doaj.org/article/dff0eaead17b49d387ed2d1c4aecb7382018-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00550-17https://doaj.org/toc/2379-5042ABSTRACT Mutations in the beta-subunit of bacterial RNA polymerase (RpoB) cause resistance to rifampin (Rifr), a critical antibiotic for treatment of multidrug-resistant Staphylococcus aureus. In vitro studies have shown that RpoB mutations confer decreased susceptibility to other antibiotics, but the clinical relevance is unknown. Here, by analyzing 7,099 S. aureus genomes, we demonstrate that the most prevalent RpoB mutations promote clinically relevant phenotypic plasticity resulting in the emergence of stable S. aureus lineages, associated with increased risk of therapeutic failure through generation of small-colony variants (SCVs) and coresistance to last-line antimicrobial agents. We found eight RpoB mutations that accounted for 93% (469/505) of the total number of Rifr mutations. The most frequently selected amino acid substitutions affecting residue 481 (H481N/Y) were associated with worldwide expansions of Rifr clones spanning decades. Recreating the H481N/Y mutations confirmed no impact on S. aureus growth, but the H481N mutation promoted the emergence of a subpopulation of stable Rifr SCVs with reduced susceptibility to vancomycin and daptomycin. Recreating the other frequent RpoB mutations showed similar impacts on resistance to these last-line agents. We found that 86% of all Rifr isolates in our global sample carried the mutations promoting cross-resistance to vancomycin and 52% to both vancomycin and daptomycin. As four of the most frequent RpoB mutations confer only low-level Rifr, equal to or below some international breakpoints, we recommend decreasing these breakpoints and reconsidering the appropriate use of rifampin to reduce the fixation and spread of these clinically deleterious mutations. IMPORTANCE Increasing antibiotic resistance in the major human pathogen Staphylococcus aureus is threatening the ability to treat patients with these infections. Recent laboratory studies suggest that mutations in the gene commonly associated with rifampin resistance may also impact susceptibility to other last-line antibiotics in S. aureus; however, the overall frequency and clinical impact of these mutations are unknown. By mining a global collection of clinical S. aureus genomes and by mutagenesis experiments, this work reveals that common rifampin-induced rpoB mutations promote phenotypic plasticity that has led to the global emergence of stable, multidrug-resistant S. aureus lineages that are associated with increased risk of therapeutic failure through coresistance to other last-line antimicrobials. We recommend decreasing susceptibility breakpoints for rifampin to allow phenotypic detection of critical rpoB mutations conferring low resistance to rifampin and reconsidering the appropriate use of rifampin to reduce the fixation and spread of these deleterious mutations globally.Romain GuérillotAnders Gonçalves da SilvaIan MonkStefano GiulieriTakehiro TomitaEloise AlisonJessica PorterSacha PidotWei GaoAnton Y. PelegTorsten SeemannTimothy P. StinearBenjamin P. HowdenAmerican Society for MicrobiologyarticleStaphylococcus aureusadaptive mutationsadaptive resistanceantibiotic resistancedrug resistance evolutiongenomicsMicrobiologyQR1-502ENmSphere, Vol 3, Iss 1 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Staphylococcus aureus adaptive mutations adaptive resistance antibiotic resistance drug resistance evolution genomics Microbiology QR1-502
spellingShingle	Staphylococcus aureus adaptive mutations adaptive resistance antibiotic resistance drug resistance evolution genomics Microbiology QR1-502 Romain Guérillot Anders Gonçalves da Silva Ian Monk Stefano Giulieri Takehiro Tomita Eloise Alison Jessica Porter Sacha Pidot Wei Gao Anton Y. Peleg Torsten Seemann Timothy P. Stinear Benjamin P. Howden Convergent Evolution Driven by Rifampin Exacerbates the Global Burden of Drug-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content>
description	ABSTRACT Mutations in the beta-subunit of bacterial RNA polymerase (RpoB) cause resistance to rifampin (Rifr), a critical antibiotic for treatment of multidrug-resistant Staphylococcus aureus. In vitro studies have shown that RpoB mutations confer decreased susceptibility to other antibiotics, but the clinical relevance is unknown. Here, by analyzing 7,099 S. aureus genomes, we demonstrate that the most prevalent RpoB mutations promote clinically relevant phenotypic plasticity resulting in the emergence of stable S. aureus lineages, associated with increased risk of therapeutic failure through generation of small-colony variants (SCVs) and coresistance to last-line antimicrobial agents. We found eight RpoB mutations that accounted for 93% (469/505) of the total number of Rifr mutations. The most frequently selected amino acid substitutions affecting residue 481 (H481N/Y) were associated with worldwide expansions of Rifr clones spanning decades. Recreating the H481N/Y mutations confirmed no impact on S. aureus growth, but the H481N mutation promoted the emergence of a subpopulation of stable Rifr SCVs with reduced susceptibility to vancomycin and daptomycin. Recreating the other frequent RpoB mutations showed similar impacts on resistance to these last-line agents. We found that 86% of all Rifr isolates in our global sample carried the mutations promoting cross-resistance to vancomycin and 52% to both vancomycin and daptomycin. As four of the most frequent RpoB mutations confer only low-level Rifr, equal to or below some international breakpoints, we recommend decreasing these breakpoints and reconsidering the appropriate use of rifampin to reduce the fixation and spread of these clinically deleterious mutations. IMPORTANCE Increasing antibiotic resistance in the major human pathogen Staphylococcus aureus is threatening the ability to treat patients with these infections. Recent laboratory studies suggest that mutations in the gene commonly associated with rifampin resistance may also impact susceptibility to other last-line antibiotics in S. aureus; however, the overall frequency and clinical impact of these mutations are unknown. By mining a global collection of clinical S. aureus genomes and by mutagenesis experiments, this work reveals that common rifampin-induced rpoB mutations promote phenotypic plasticity that has led to the global emergence of stable, multidrug-resistant S. aureus lineages that are associated with increased risk of therapeutic failure through coresistance to other last-line antimicrobials. We recommend decreasing susceptibility breakpoints for rifampin to allow phenotypic detection of critical rpoB mutations conferring low resistance to rifampin and reconsidering the appropriate use of rifampin to reduce the fixation and spread of these deleterious mutations globally.
format	article
author	Romain Guérillot Anders Gonçalves da Silva Ian Monk Stefano Giulieri Takehiro Tomita Eloise Alison Jessica Porter Sacha Pidot Wei Gao Anton Y. Peleg Torsten Seemann Timothy P. Stinear Benjamin P. Howden
author_facet	Romain Guérillot Anders Gonçalves da Silva Ian Monk Stefano Giulieri Takehiro Tomita Eloise Alison Jessica Porter Sacha Pidot Wei Gao Anton Y. Peleg Torsten Seemann Timothy P. Stinear Benjamin P. Howden
author_sort	Romain Guérillot
title	Convergent Evolution Driven by Rifampin Exacerbates the Global Burden of Drug-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_short	Convergent Evolution Driven by Rifampin Exacerbates the Global Burden of Drug-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_full	Convergent Evolution Driven by Rifampin Exacerbates the Global Burden of Drug-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_fullStr	Convergent Evolution Driven by Rifampin Exacerbates the Global Burden of Drug-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_full_unstemmed	Convergent Evolution Driven by Rifampin Exacerbates the Global Burden of Drug-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_sort	convergent evolution driven by rifampin exacerbates the global burden of drug-resistant <named-content content-type="genus-species">staphylococcus aureus</named-content>
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/dff0eaead17b49d387ed2d1c4aecb738
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Convergent Evolution Driven by Rifampin Exacerbates the Global Burden of Drug-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content>

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