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Analysis of the Impact of Rosuvastatin on Bacterial Mevalonate Production Using a UPLC-Mass Spectrometry Approach

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Abstract

Statins are widely prescribed cholesterol-lowering medications and act through inhibition of the human enzyme 3-methylglutaryl coenzyme A reductase (HMG-R) which produces mevalonate (MVAL), a key substrate for cholesterol biosynthesis. Some important microbial species also express an isoform of HMG-R; however, the nature of the interaction between statins and bacteria is currently unclear and studies would benefit from protocols to quantify MVAL in complex microbial environments. The objective of this study was to develop a protocol for the analytical quantification of MVAL in bacterial systems and to utilise this approach to analyse the effects of Rosuvastatin (RSV) on bacterial MVAL formation. To determine the effective concentration range of RSV, we examined the dose-dependent inhibition of growth in the HMG-R+ bacterial pathogens Listeria monocytogenes, Staphylococcus aureus and Enterococcus faecium at various concentrations of pure RSV. Growth inhibition generally correlated with a reduction in bacterial MVAL levels, particularly in culture supernatants at high RSV concentrations, as determined using our ultra-performance liquid chromatography mass spectrometry protocol. This work therefore outlines a refined protocol for the analysis of MVAL in microbial cultures and provides evidence for statin-mediated inhibition of bacterial HMG-R. Furthermore, we show that MVAL is readily transported and secreted from bacterial cells into the growth media.

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Acknowledgments

J.A.N. was funded by an EMBARK postgraduate research scholarship from the Irish Research Council for Science Engineering and Technology (IRCSET). The mass spectrometry instrument and analysis was funded under the Higher Education Authority Programme for Research in Third Level Institutions (PRTLI), cycle 4 and co-funded under the European Regional Development Fund. This publication has emanated from research conducted with the financial support of Science Foundation Ireland (SFI) under Grant Number SFI/12/RC/2273.

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Author notes

  1. M. Kinsella

    Present address: Department of Science, School of Science & Computing, Waterford Institute of Technology, Waterford, Ireland

Authors and Affiliations

  1. APC Microbiome Institute, University College Cork, Cork, Ireland

    J. A. Nolan, C. Hill, S. A. Joyce & C. G. M. Gahan

  2. School of Microbiology, University College Cork, Cork, Ireland

    J. A. Nolan, C. Hill & C. G. M. Gahan

  3. School of Food and Nutritional Sciences, University College Cork, Cork, Ireland

    M. Kinsella

  4. School of Biochemistry & Cell Biology, University College Cork, Cork, Ireland

    S. A. Joyce

  5. School of Pharmacy, University College Cork, Cork, Ireland

    C. G. M. Gahan

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  1. J. A. Nolan
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  2. M. Kinsella
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  3. C. Hill
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Corresponding authors

Correspondence to S. A. Joyce or C. G. M. Gahan.

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No conflict of interest declared.

Electronic supplementary material

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284_2016_1014_MOESM1_ESM.docx

Figure S1. UPLC-MS standard curve of MVAL. Figure S2. Elution of MVAL at 2.1 mins at 12.5 ng/ml giving a limit of detection (LOD) of 3.125 ng/ml. Figure S3. CLUSTAL (MUSCLE) alignment of C. kroppenstedtii (Class I HMG-R) against S. aureus (Class II HMG-R) revealed low sequence identity (20.06%) and regions of dissimilarity. Supplementary material 1 (DOCX 468 kb)

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Nolan, J.A., Kinsella, M., Hill, C. et al. Analysis of the Impact of Rosuvastatin on Bacterial Mevalonate Production Using a UPLC-Mass Spectrometry Approach. Curr Microbiol 73, 1–8 (2016). https://doi.org/10.1007/s00284-016-1014-z

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  • DOI: https://doi.org/10.1007/s00284-016-1014-z

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