Convergent evolution driven by rifampin exacerbates the global burden of drug-resistant Staphylococcus aureus

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

Research output: Contribution to journalArticleResearchpeer-review

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 lastline 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.

Original languageEnglish
Article numbere00550-17
JournalmSphere
Volume3
Issue number1
DOIs
Publication statusPublished - 1 Jan 2018

Keywords

  • Adaptive mutations
  • Adaptive resistance
  • Antibiotic resistance
  • Drug resistance evolution
  • Genomics
  • Staphylococcus aureus
  • Vancomycin

Cite this

Guérillot, R., da Silva, A. G., Monk, I., Giulieri, S., Tomita, T., Alison, E., ... Howden, B. P. (2018). Convergent evolution driven by rifampin exacerbates the global burden of drug-resistant Staphylococcus aureus. mSphere, 3(1), [e00550-17]. https://doi.org/10.1128/mSphere.00550-17
Guérillot, Romain ; da Silva, Anders Gonçalves ; Monk, Ian ; Giulieri, Stefano ; Tomita, Takehiro ; Alison, Eloise ; Porter, Jessica ; Pidot, Sacha ; Gao, Wei ; Peleg, Anton Y. ; Seemann, Torsten ; Stinear, Timothy P. ; Howden, Benjamin P. / Convergent evolution driven by rifampin exacerbates the global burden of drug-resistant Staphylococcus aureus. In: mSphere. 2018 ; Vol. 3, No. 1.
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title = "Convergent evolution driven by rifampin exacerbates the global burden of drug-resistant Staphylococcus aureus",
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 lastline 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.",
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author = "Romain Gu{\'e}rillot and {da Silva}, {Anders Gon{\cc}alves} and Ian Monk and Stefano Giulieri and Takehiro Tomita and Eloise Alison and Jessica Porter and Sacha Pidot and Wei Gao and Peleg, {Anton Y.} and Torsten Seemann and Stinear, {Timothy P.} and Howden, {Benjamin P.}",
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Guérillot, R, da Silva, AG, Monk, I, Giulieri, S, Tomita, T, Alison, E, Porter, J, Pidot, S, Gao, W, Peleg, AY, Seemann, T, Stinear, TP & Howden, BP 2018, 'Convergent evolution driven by rifampin exacerbates the global burden of drug-resistant Staphylococcus aureus' mSphere, vol. 3, no. 1, e00550-17. https://doi.org/10.1128/mSphere.00550-17

Convergent evolution driven by rifampin exacerbates the global burden of drug-resistant Staphylococcus aureus. / Guérillot, Romain; da Silva, Anders Gonçalves; Monk, Ian; Giulieri, Stefano; Tomita, Takehiro; Alison, Eloise; Porter, Jessica; Pidot, Sacha; Gao, Wei; Peleg, Anton Y.; Seemann, Torsten; Stinear, Timothy P.; Howden, Benjamin P.

In: mSphere, Vol. 3, No. 1, e00550-17, 01.01.2018.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Convergent evolution driven by rifampin exacerbates the global burden of drug-resistant Staphylococcus aureus

AU - Guérillot, Romain

AU - da Silva, Anders Gonçalves

AU - Monk, Ian

AU - Giulieri, Stefano

AU - Tomita, Takehiro

AU - Alison, Eloise

AU - Porter, Jessica

AU - Pidot, Sacha

AU - Gao, Wei

AU - Peleg, Anton Y.

AU - Seemann, Torsten

AU - Stinear, Timothy P.

AU - Howden, Benjamin P.

PY - 2018/1/1

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N2 - 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 lastline 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.

AB - 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 lastline 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.

KW - Adaptive mutations

KW - Adaptive resistance

KW - Antibiotic resistance

KW - Drug resistance evolution

KW - Genomics

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KW - Vancomycin

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Guérillot R, da Silva AG, Monk I, Giulieri S, Tomita T, Alison E et al. Convergent evolution driven by rifampin exacerbates the global burden of drug-resistant Staphylococcus aureus. mSphere. 2018 Jan 1;3(1). e00550-17. https://doi.org/10.1128/mSphere.00550-17