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Epistasis analysis uncovers hidden antibiotic resistance-associated fitness costs hampering the evolution of MRSA

Yokoyama, Maho ; Stevens, Emily ; Laabei, Maisem LU ; Bacon, Leann ; Heesom, Kate ; Bayliss, Sion ; Ooi, Nicola ; O'Neill, Alex J. ; Murray, Ewan and Williams, Paul , et al. (2018) In Genome Biology 19(1).
Abstract

Background: Fitness costs imposed on bacteria by antibiotic resistance mechanisms are believed to hamper their dissemination. The scale of these costs is highly variable. Some, including resistance of Staphylococcus aureus to the clinically important antibiotic mupirocin, have been reported as being cost-free, which suggests that there are few barriers preventing their global spread. However, this is not supported by surveillance data in healthy communities, which indicate that this resistance mechanism is relatively unsuccessful. Results: Epistasis analysis on two collections of MRSA provides an explanation for this discord, where the mupirocin resistance-conferring mutation of the ileS gene appears to affect the levels of toxins... (More)

Background: Fitness costs imposed on bacteria by antibiotic resistance mechanisms are believed to hamper their dissemination. The scale of these costs is highly variable. Some, including resistance of Staphylococcus aureus to the clinically important antibiotic mupirocin, have been reported as being cost-free, which suggests that there are few barriers preventing their global spread. However, this is not supported by surveillance data in healthy communities, which indicate that this resistance mechanism is relatively unsuccessful. Results: Epistasis analysis on two collections of MRSA provides an explanation for this discord, where the mupirocin resistance-conferring mutation of the ileS gene appears to affect the levels of toxins produced by S. aureus when combined with specific polymorphisms at other loci. Proteomic analysis demonstrates that the activity of the secretory apparatus of the PSM family of toxins is affected by mupirocin resistance. As an energetically costly activity, this reduction in toxicity masks the fitness costs associated with this resistance mutation, a cost that becomes apparent when toxin production becomes necessary. This hidden fitness cost provides a likely explanation for why this mupirocin-resistance mechanism is not more prevalent, given the widespread use of this antibiotic. Conclusions: With dwindling pools of antibiotics available for use, information on the fitness consequences of the acquisition of resistance may need to be considered when designing antibiotic prescribing policies. However, this study suggests there are levels of depth that we do not understand, and that holistic, surveillance and functional genomics approaches are required to gain this crucial information.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Epistasis, Fitness costs, GWAS, MRSA, Mupirocin resistance
in
Genome Biology
volume
19
issue
1
article number
94
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85050259073
  • pmid:30021593
ISSN
1474-7596
DOI
10.1186/s13059-018-1469-2
language
English
LU publication?
yes
id
4cfcd5ab-42e7-4089-8704-d06ab0fdd517
date added to LUP
2018-08-28 14:45:50
date last changed
2021-10-06 05:42:01
@article{4cfcd5ab-42e7-4089-8704-d06ab0fdd517,
  abstract     = {<p>Background: Fitness costs imposed on bacteria by antibiotic resistance mechanisms are believed to hamper their dissemination. The scale of these costs is highly variable. Some, including resistance of Staphylococcus aureus to the clinically important antibiotic mupirocin, have been reported as being cost-free, which suggests that there are few barriers preventing their global spread. However, this is not supported by surveillance data in healthy communities, which indicate that this resistance mechanism is relatively unsuccessful. Results: Epistasis analysis on two collections of MRSA provides an explanation for this discord, where the mupirocin resistance-conferring mutation of the ileS gene appears to affect the levels of toxins produced by S. aureus when combined with specific polymorphisms at other loci. Proteomic analysis demonstrates that the activity of the secretory apparatus of the PSM family of toxins is affected by mupirocin resistance. As an energetically costly activity, this reduction in toxicity masks the fitness costs associated with this resistance mutation, a cost that becomes apparent when toxin production becomes necessary. This hidden fitness cost provides a likely explanation for why this mupirocin-resistance mechanism is not more prevalent, given the widespread use of this antibiotic. Conclusions: With dwindling pools of antibiotics available for use, information on the fitness consequences of the acquisition of resistance may need to be considered when designing antibiotic prescribing policies. However, this study suggests there are levels of depth that we do not understand, and that holistic, surveillance and functional genomics approaches are required to gain this crucial information.</p>},
  author       = {Yokoyama, Maho and Stevens, Emily and Laabei, Maisem and Bacon, Leann and Heesom, Kate and Bayliss, Sion and Ooi, Nicola and O'Neill, Alex J. and Murray, Ewan and Williams, Paul and Lubben, Anneke and Reeksting, Shaun and Meric, Guillaume and Pascoe, Ben and Sheppard, Samuel K. and Recker, Mario and Hurst, Laurence D. and Massey, Ruth C.},
  issn         = {1474-7596},
  language     = {eng},
  month        = {07},
  number       = {1},
  publisher    = {BioMed Central (BMC)},
  series       = {Genome Biology},
  title        = {Epistasis analysis uncovers hidden antibiotic resistance-associated fitness costs hampering the evolution of MRSA},
  url          = {http://dx.doi.org/10.1186/s13059-018-1469-2},
  doi          = {10.1186/s13059-018-1469-2},
  volume       = {19},
  year         = {2018},
}