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

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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, 18.07.2018.

Research output: Contribution to journalArticle

Harvard

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

APA

Yokoyama, M., Stevens, E., Laabei, M., Bacon, L., Heesom, K., Bayliss, S., Ooi, N., O'Neill, A. J., Murray, E., Williams, P., Lubben, A., Reeksting, S., Meric, G., Pascoe, B., Sheppard, S. K., Recker, M., Hurst, L. D., & Massey, R. C. (2018). Epistasis analysis uncovers hidden antibiotic resistance-associated fitness costs hampering the evolution of MRSA. Genome Biology, 19(1), [94]. https://doi.org/10.1186/s13059-018-1469-2

CBE

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. 19(1):Article 94. https://doi.org/10.1186/s13059-018-1469-2

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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.

RIS

TY - JOUR

T1 - Epistasis analysis uncovers hidden antibiotic resistance-associated fitness costs hampering the evolution of MRSA

AU - Yokoyama, Maho

AU - Stevens, Emily

AU - Laabei, Maisem

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.

PY - 2018/7/18

Y1 - 2018/7/18

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.

KW - Epistasis

KW - Fitness costs

KW - GWAS

KW - MRSA

KW - Mupirocin resistance

UR - http://www.scopus.com/inward/record.url?scp=85050259073&partnerID=8YFLogxK

U2 - 10.1186/s13059-018-1469-2

DO - 10.1186/s13059-018-1469-2

M3 - Article

C2 - 30021593

AN - SCOPUS:85050259073

VL - 19

JO - Genome Biology

JF - Genome Biology

SN - 1474-7596

IS - 1

M1 - 94

ER -