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

Maho Yokoyama, Emily Stevens, Maisem Laabei, Leann Bacon, Kate Heesom, Sion Bayliss, Nicola Ooi, Alex J O'Neill, Ewan Murray, Paul Williams, Anneke Lubben, Shaun Reeksting, Guillaume Meric, Ben Pascoe, Samuel K Sheppard, Mario Recker, Laurence D Hurst, Ruth C Massey

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 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.

LanguageEnglish
Article number94
JournalGenome Biology
Volume19
Issue number1
Early online date18 Jul 2018
DOIs
StatusPublished - Jul 2018

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epistasis
antibiotic resistance
Methicillin-Resistant Staphylococcus aureus
Microbial Drug Resistance
Mupirocin
fitness
resistance mechanisms
antibiotics
Costs and Cost Analysis
toxins
cost
toxin
Anti-Bacterial Agents
Staphylococcus aureus
mutation
monitoring
proteomics
Mutation
genetic polymorphism
Masks

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Epistasis analysis uncovers hidden antibiotic resistance-associated fitness costs hampering the evolution of MRSA. / Yokoyama, Maho; Stevens, Emily; Laabei, Maisem; Bacon, Leann; Heesom, Kate; Bayliss, Sion; Ooi, Nicola; O'Neill, Alex J; Murray, Ewan; Williams, Paul; Lubben, Anneke; Reeksting, Shaun; Meric, Guillaume; Pascoe, Ben; Sheppard, Samuel K; Recker, Mario; Hurst, Laurence D; Massey, Ruth C.

In: Genome Biology, Vol. 19, No. 1, 94, 07.2018.

Research output: Contribution to journalArticle

Yokoyama, M, Stevens, E, Laabei, M, Bacon, L, Heesom, K, Bayliss, S, Ooi, N, O'Neill, AJ, Murray, E, Williams, P, Lubben, A, Reeksting, S, Meric, G, Pascoe, B, Sheppard, SK, Recker, M, Hurst, LD & Massey, RC 2018, 'Epistasis analysis uncovers hidden antibiotic resistance-associated fitness costs hampering the evolution of MRSA', Genome Biology, vol. 19, no. 1, 94. https://doi.org/10.1186/s13059-018-1469-2
Yokoyama, Maho ; Stevens, Emily ; Laabei, Maisem ; Bacon, Leann ; Heesom, Kate ; Bayliss, Sion ; Ooi, Nicola ; O'Neill, Alex J ; Murray, Ewan ; Williams, Paul ; Lubben, Anneke ; Reeksting, Shaun ; Meric, Guillaume ; Pascoe, Ben ; Sheppard, Samuel K ; Recker, Mario ; Hurst, Laurence D ; Massey, Ruth C. / Epistasis analysis uncovers hidden antibiotic resistance-associated fitness costs hampering the evolution of MRSA. In: Genome Biology. 2018 ; Vol. 19, No. 1.
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AU - Bacon, Leann

AU - Heesom, Kate

AU - Bayliss, Sion

AU - Ooi, Nicola

AU - O'Neill, Alex J

AU - Murray, Ewan

AU - Williams, Paul

AU - Lubben, Anneke

AU - Reeksting, Shaun

AU - Meric, Guillaume

AU - Pascoe, Ben

AU - Sheppard, Samuel K

AU - Recker, Mario

AU - Hurst, Laurence D

AU - Massey, Ruth C

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N2 - 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.

AB - 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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