2-Alkyl-4-quinolone quorum sensing molecules are biomarkers for culture-independent Pseudomonas aeruginosa burden in adults with cystic fibrosis

Nur Masirah M. Zain; Karmel Webb; Iain Stewart; Nigel Halliday; David A. Barrett; Edward F. Nash; Joanna L. Whitehouse; David Honeybourne; Alan R. Smyth; Douglas L. Forrester; Alan J. Knox; Paul Williams; Andrew Fogarty; Miguel Cámara; Kenneth D. Bruce; Helen L. Barr

doi:10.1099/jmm.0.001420

2-Alkyl-4-quinolone quorum sensing molecules are biomarkers for culture-independent Pseudomonas aeruginosa burden in adults with cystic fibrosis

Nur Masirah M. Zain^*, Karmel Webb, Iain Stewart, Nigel Halliday, David A. Barrett, Edward F. Nash, Joanna L. Whitehouse, David Honeybourne, Alan R. Smyth, Douglas L. Forrester, Alan J. Knox, Paul Williams, Andrew Fogarty, Miguel Cámara, Kenneth D. Bruce, Helen L. Barr

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

Abstract

Introduction. Pseudomonas aeruginosa produces quorum sensing signalling molecules including 2-alkyl-4-quinolones (AQs), which regulate virulence factor production in the cystic fibrosis (CF) airways.

Hypothesis/Gap statement. Culture can lead to condition-dependent artefacts which may limit the potential insights and applications of AQs as minimally-invasive biomarkers of bacterial load.

Aim. We aimed to use culture-independent methods to explore the correlations between AQ levels and live P. aeruginosa load in adults with CF.

Methodology. Seventy-five sputum samples at clinical stability and 48 paired sputum samples obtained at the beginning and end of IV antibiotics for a pulmonary exacerbation in adults with CF were processed using a viable cell separation technique followed by quantitative P. aeruginosa polymerase chain reaction (qPCR). Live P. aeruginosa qPCR load was compared with the concentrations of three AQs (HHQ, NHQ and HQNO) detected in sputum, plasma and urine.

Results. At clinical stability and the beginning of IV antibiotics for pulmonary exacerbation, HHQ, NHQ and HQNO measured in sputum, plasma and urine were consistently positively correlated with live P. aeruginosa qPCR load in sputum, compared to culture. Following systemic antibiotics live P. aeruginosa qPCR load decreased significantly (P<0.001) and was correlated with a reduction in plasma NHQ (plasma: r=0.463, P=0.003).

Conclusion. In adults with CF, AQ concentrations correlated more strongly with live P. aeruginosa bacterial load measured by qPCR compared to traditional culture. Prospective studies are required to assess the potential of systemic AQs as biomarkers of P. aeruginosa bacterial burden.

Original language	English
Article number	001420
Number of pages	9
Journal	Journal of Medical Microbiology
Volume	70
Issue number	10
DOIs	https://doi.org/10.1099/jmm.0.001420
Publication status	Published - 01 Oct 2021
Externally published	Yes

Bibliographical note

Funding Information:
Funding contributions from NIHR Nottingham Biomedical Research Centre and the U.K. Medical Research Council (grant number G0801558/1).

Funding Information:
M.C. and P.W., are partly funded by the National Biofilms Innovation Centre (NBIC) which is an Innovation and Knowledge Centre funded by the Biotechnology and Biological Sciences Research Council, InnovateUK and Hartree Centre (Award Number BB/R012415/1). ARS received research grant and consultancy fund from Vertex, and speaker honoraria and expenses from Teva and Novartis. D.A.B., A.R.S., D.L.F., A.F., M.C. and H.L.B., have a patent issued ‘Alkyl-quinolones as biomarkers of Pseudomonas aeruginosa infection and uses thereof-PCT/GB2014/051458’. N.H. and P.W., has a patent WO/2014/184535 pending. N.M.Z., K.W., I.S., E.F.N., J.L.W., D.H., A.J.K. and K.D.B., declared that there are no conflict of interest.

Publisher Copyright:
© 2021 The Authors

Keywords

Alkyl-quinolones
Cystic fibrosis
PMA-qPCR
Pseudomonas aeruginosa
Quorum sensing molecules

ASJC Scopus subject areas

Microbiology
Microbiology (medical)

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Cite this

Zain, N. M. M., Webb, K., Stewart, I., Halliday, N., Barrett, D. A., Nash, E. F., Whitehouse, J. L., Honeybourne, D., Smyth, A. R., Forrester, D. L., Knox, A. J., Williams, P., Fogarty, A., Cámara, M., Bruce, K. D., & Barr, H. L. (2021). 2-Alkyl-4-quinolone quorum sensing molecules are biomarkers for culture-independent Pseudomonas aeruginosa burden in adults with cystic fibrosis. Journal of Medical Microbiology, 70(10), Article 001420. https://doi.org/10.1099/jmm.0.001420

@article{a96cd4840cbf4b828ba308bf74d78c55,

title = "2-Alkyl-4-quinolone quorum sensing molecules are biomarkers for culture-independent Pseudomonas aeruginosa burden in adults with cystic fibrosis",

abstract = "Introduction. Pseudomonas aeruginosa produces quorum sensing signalling molecules including 2-alkyl-4-quinolones (AQs), which regulate virulence factor production in the cystic fibrosis (CF) airways.Hypothesis/Gap statement. Culture can lead to condition-dependent artefacts which may limit the potential insights and applications of AQs as minimally-invasive biomarkers of bacterial load.Aim. We aimed to use culture-independent methods to explore the correlations between AQ levels and live P. aeruginosa load in adults with CF.Methodology. Seventy-five sputum samples at clinical stability and 48 paired sputum samples obtained at the beginning and end of IV antibiotics for a pulmonary exacerbation in adults with CF were processed using a viable cell separation technique followed by quantitative P. aeruginosa polymerase chain reaction (qPCR). Live P. aeruginosa qPCR load was compared with the concentrations of three AQs (HHQ, NHQ and HQNO) detected in sputum, plasma and urine.Results. At clinical stability and the beginning of IV antibiotics for pulmonary exacerbation, HHQ, NHQ and HQNO measured in sputum, plasma and urine were consistently positively correlated with live P. aeruginosa qPCR load in sputum, compared to culture. Following systemic antibiotics live P. aeruginosa qPCR load decreased significantly (P<0.001) and was correlated with a reduction in plasma NHQ (plasma: r=0.463, P=0.003).Conclusion. In adults with CF, AQ concentrations correlated more strongly with live P. aeruginosa bacterial load measured by qPCR compared to traditional culture. Prospective studies are required to assess the potential of systemic AQs as biomarkers of P. aeruginosa bacterial burden.",

keywords = "Alkyl-quinolones, Cystic fibrosis, PMA-qPCR, Pseudomonas aeruginosa, Quorum sensing molecules",

author = "Zain, {Nur Masirah M.} and Karmel Webb and Iain Stewart and Nigel Halliday and Barrett, {David A.} and Nash, {Edward F.} and Whitehouse, {Joanna L.} and David Honeybourne and Smyth, {Alan R.} and Forrester, {Douglas L.} and Knox, {Alan J.} and Paul Williams and Andrew Fogarty and Miguel C{\'a}mara and Bruce, {Kenneth D.} and Barr, {Helen L.}",

note = "Funding Information: Funding contributions from NIHR Nottingham Biomedical Research Centre and the U.K. Medical Research Council (grant number G0801558/1). Funding Information: M.C. and P.W., are partly funded by the National Biofilms Innovation Centre (NBIC) which is an Innovation and Knowledge Centre funded by the Biotechnology and Biological Sciences Research Council, InnovateUK and Hartree Centre (Award Number BB/R012415/1). ARS received research grant and consultancy fund from Vertex, and speaker honoraria and expenses from Teva and Novartis. D.A.B., A.R.S., D.L.F., A.F., M.C. and H.L.B., have a patent issued {\textquoteleft}Alkyl-quinolones as biomarkers of Pseudomonas aeruginosa infection and uses thereof-PCT/GB2014/051458{\textquoteright}. N.H. and P.W., has a patent WO/2014/184535 pending. N.M.Z., K.W., I.S., E.F.N., J.L.W., D.H., A.J.K. and K.D.B., declared that there are no conflict of interest. Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = oct,

day = "1",

doi = "10.1099/jmm.0.001420",

language = "English",

volume = "70",

journal = "Journal of Medical Microbiology",

issn = "0022-2615",

publisher = "Microbiology Society",

number = "10",

}

Zain, NMM, Webb, K, Stewart, I, Halliday, N, Barrett, DA, Nash, EF, Whitehouse, JL, Honeybourne, D, Smyth, AR, Forrester, DL, Knox, AJ, Williams, P, Fogarty, A, Cámara, M, Bruce, KD & Barr, HL 2021, '2-Alkyl-4-quinolone quorum sensing molecules are biomarkers for culture-independent Pseudomonas aeruginosa burden in adults with cystic fibrosis', Journal of Medical Microbiology, vol. 70, no. 10, 001420. https://doi.org/10.1099/jmm.0.001420

TY - JOUR

T1 - 2-Alkyl-4-quinolone quorum sensing molecules are biomarkers for culture-independent Pseudomonas aeruginosa burden in adults with cystic fibrosis

AU - Zain, Nur Masirah M.

AU - Webb, Karmel

AU - Stewart, Iain

AU - Halliday, Nigel

AU - Barrett, David A.

AU - Nash, Edward F.

AU - Whitehouse, Joanna L.

AU - Honeybourne, David

AU - Smyth, Alan R.

AU - Forrester, Douglas L.

AU - Knox, Alan J.

AU - Williams, Paul

AU - Fogarty, Andrew

AU - Cámara, Miguel

AU - Bruce, Kenneth D.

AU - Barr, Helen L.

N1 - Funding Information: Funding contributions from NIHR Nottingham Biomedical Research Centre and the U.K. Medical Research Council (grant number G0801558/1). Funding Information: M.C. and P.W., are partly funded by the National Biofilms Innovation Centre (NBIC) which is an Innovation and Knowledge Centre funded by the Biotechnology and Biological Sciences Research Council, InnovateUK and Hartree Centre (Award Number BB/R012415/1). ARS received research grant and consultancy fund from Vertex, and speaker honoraria and expenses from Teva and Novartis. D.A.B., A.R.S., D.L.F., A.F., M.C. and H.L.B., have a patent issued ‘Alkyl-quinolones as biomarkers of Pseudomonas aeruginosa infection and uses thereof-PCT/GB2014/051458’. N.H. and P.W., has a patent WO/2014/184535 pending. N.M.Z., K.W., I.S., E.F.N., J.L.W., D.H., A.J.K. and K.D.B., declared that there are no conflict of interest. Publisher Copyright: © 2021 The Authors

PY - 2021/10/1

Y1 - 2021/10/1

N2 - Introduction. Pseudomonas aeruginosa produces quorum sensing signalling molecules including 2-alkyl-4-quinolones (AQs), which regulate virulence factor production in the cystic fibrosis (CF) airways.Hypothesis/Gap statement. Culture can lead to condition-dependent artefacts which may limit the potential insights and applications of AQs as minimally-invasive biomarkers of bacterial load.Aim. We aimed to use culture-independent methods to explore the correlations between AQ levels and live P. aeruginosa load in adults with CF.Methodology. Seventy-five sputum samples at clinical stability and 48 paired sputum samples obtained at the beginning and end of IV antibiotics for a pulmonary exacerbation in adults with CF were processed using a viable cell separation technique followed by quantitative P. aeruginosa polymerase chain reaction (qPCR). Live P. aeruginosa qPCR load was compared with the concentrations of three AQs (HHQ, NHQ and HQNO) detected in sputum, plasma and urine.Results. At clinical stability and the beginning of IV antibiotics for pulmonary exacerbation, HHQ, NHQ and HQNO measured in sputum, plasma and urine were consistently positively correlated with live P. aeruginosa qPCR load in sputum, compared to culture. Following systemic antibiotics live P. aeruginosa qPCR load decreased significantly (P<0.001) and was correlated with a reduction in plasma NHQ (plasma: r=0.463, P=0.003).Conclusion. In adults with CF, AQ concentrations correlated more strongly with live P. aeruginosa bacterial load measured by qPCR compared to traditional culture. Prospective studies are required to assess the potential of systemic AQs as biomarkers of P. aeruginosa bacterial burden.

AB - Introduction. Pseudomonas aeruginosa produces quorum sensing signalling molecules including 2-alkyl-4-quinolones (AQs), which regulate virulence factor production in the cystic fibrosis (CF) airways.Hypothesis/Gap statement. Culture can lead to condition-dependent artefacts which may limit the potential insights and applications of AQs as minimally-invasive biomarkers of bacterial load.Aim. We aimed to use culture-independent methods to explore the correlations between AQ levels and live P. aeruginosa load in adults with CF.Methodology. Seventy-five sputum samples at clinical stability and 48 paired sputum samples obtained at the beginning and end of IV antibiotics for a pulmonary exacerbation in adults with CF were processed using a viable cell separation technique followed by quantitative P. aeruginosa polymerase chain reaction (qPCR). Live P. aeruginosa qPCR load was compared with the concentrations of three AQs (HHQ, NHQ and HQNO) detected in sputum, plasma and urine.Results. At clinical stability and the beginning of IV antibiotics for pulmonary exacerbation, HHQ, NHQ and HQNO measured in sputum, plasma and urine were consistently positively correlated with live P. aeruginosa qPCR load in sputum, compared to culture. Following systemic antibiotics live P. aeruginosa qPCR load decreased significantly (P<0.001) and was correlated with a reduction in plasma NHQ (plasma: r=0.463, P=0.003).Conclusion. In adults with CF, AQ concentrations correlated more strongly with live P. aeruginosa bacterial load measured by qPCR compared to traditional culture. Prospective studies are required to assess the potential of systemic AQs as biomarkers of P. aeruginosa bacterial burden.

KW - Alkyl-quinolones

KW - Cystic fibrosis

KW - PMA-qPCR

KW - Pseudomonas aeruginosa

KW - Quorum sensing molecules

U2 - 10.1099/jmm.0.001420

DO - 10.1099/jmm.0.001420

M3 - Article

C2 - 34596013

AN - SCOPUS:85117554749

SN - 0022-2615

VL - 70

JO - Journal of Medical Microbiology

JF - Journal of Medical Microbiology

IS - 10

M1 - 001420

ER -

2-Alkyl-4-quinolone quorum sensing molecules are biomarkers for culture-independent Pseudomonas aeruginosa burden in adults with cystic fibrosis

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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