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Evaluating the level of nitroreductase activity in clinical Klebsiella pneumoniae isolates to support strategies for nitro drug and prodrug development

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Evaluating the level of nitroreductase activity in clinical Klebsiella pneumoniae isolates to support strategies for nitro drug and prodrug development. / Wand, Matthew E.; Taylor, Holly V.; Auer, Jennifer L.; Bock, Lucy J.; Hind, Charlotte K.; Jamshidi, Shirin; Rahman, Khondaker Miraz; Sutton, J. Mark.

In: INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, Vol. 54, No. 5, 01.11.2019, p. 538-546.

Research output: Contribution to journalArticle

Harvard

Wand, ME, Taylor, HV, Auer, JL, Bock, LJ, Hind, CK, Jamshidi, S, Rahman, KM & Sutton, JM 2019, 'Evaluating the level of nitroreductase activity in clinical Klebsiella pneumoniae isolates to support strategies for nitro drug and prodrug development', INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, vol. 54, no. 5, pp. 538-546. https://doi.org/10.1016/j.ijantimicag.2019.08.009

APA

Wand, M. E., Taylor, H. V., Auer, J. L., Bock, L. J., Hind, C. K., Jamshidi, S., ... Sutton, J. M. (2019). Evaluating the level of nitroreductase activity in clinical Klebsiella pneumoniae isolates to support strategies for nitro drug and prodrug development. INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, 54(5), 538-546. https://doi.org/10.1016/j.ijantimicag.2019.08.009

Vancouver

Wand ME, Taylor HV, Auer JL, Bock LJ, Hind CK, Jamshidi S et al. Evaluating the level of nitroreductase activity in clinical Klebsiella pneumoniae isolates to support strategies for nitro drug and prodrug development. INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS. 2019 Nov 1;54(5):538-546. https://doi.org/10.1016/j.ijantimicag.2019.08.009

Author

Wand, Matthew E. ; Taylor, Holly V. ; Auer, Jennifer L. ; Bock, Lucy J. ; Hind, Charlotte K. ; Jamshidi, Shirin ; Rahman, Khondaker Miraz ; Sutton, J. Mark. / Evaluating the level of nitroreductase activity in clinical Klebsiella pneumoniae isolates to support strategies for nitro drug and prodrug development. In: INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS. 2019 ; Vol. 54, No. 5. pp. 538-546.

Bibtex Download

@article{6f38e8caa33a4b409d9e6d914d36a41f,
title = "Evaluating the level of nitroreductase activity in clinical Klebsiella pneumoniae isolates to support strategies for nitro drug and prodrug development",
abstract = "To understand the potential utility of novel nitroreductase (NR)-activated prodrugs, NR enzyme activity was assessed in clinical Klebsiella pneumoniae isolates using a NR-activated fluorescent probe. NR activity was constant throughout the bacterial growth cycle, but individual K. pneumoniae isolates exhibited a wide range of NR activity levels. The genes of major NR enzymes (nfsA and nfnB) showed a number of sequence variants. Aside from a C-terminal extension of NfnB, which may be responsible for lower NR activity in specific isolates, the genetic differences did not explain the variation in activity. Analysis of important clinical strains (ST11, ST258, ST14 and ST101) showed significant variation in NR activity between isolates within the same sequence type despite conservation of nfsA/nfnB sequences. Addition of methyl viologen (MV), a known activator of soxRS, caused a significant increase in NR activity for all strains, with proportionally larger increases in activity seen for strains with low uninduced NR levels. Real-time PCR on selected strains following exposure to MV showed upregulation of soxS (15–32-fold) and nfsA (5–22-fold) in all strains tested. Expression of nfnB was upregulated 2–5-fold in 4/6 strains tested. High levels of NR activity in the absence of MV activation correlated with nitrofurantoin susceptibility. These data provide evidence that NR gene mutations and regulatory pathways influence NR activity in K. pneumoniae isolates and this is likely to impact treatment efficacy with novel nitro-containing drugs or prodrugs.",
keywords = "Klebsiella pneumoniae, Methyl viologen, nfsA, Nitroreductase, Prodrug, soxRS",
author = "Wand, {Matthew E.} and Taylor, {Holly V.} and Auer, {Jennifer L.} and Bock, {Lucy J.} and Hind, {Charlotte K.} and Shirin Jamshidi and Rahman, {Khondaker Miraz} and Sutton, {J. Mark}",
year = "2019",
month = "11",
day = "1",
doi = "10.1016/j.ijantimicag.2019.08.009",
language = "English",
volume = "54",
pages = "538--546",
journal = "INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS",
issn = "0924-8579",
publisher = "Elsevier",
number = "5",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - Evaluating the level of nitroreductase activity in clinical Klebsiella pneumoniae isolates to support strategies for nitro drug and prodrug development

AU - Wand, Matthew E.

AU - Taylor, Holly V.

AU - Auer, Jennifer L.

AU - Bock, Lucy J.

AU - Hind, Charlotte K.

AU - Jamshidi, Shirin

AU - Rahman, Khondaker Miraz

AU - Sutton, J. Mark

PY - 2019/11/1

Y1 - 2019/11/1

N2 - To understand the potential utility of novel nitroreductase (NR)-activated prodrugs, NR enzyme activity was assessed in clinical Klebsiella pneumoniae isolates using a NR-activated fluorescent probe. NR activity was constant throughout the bacterial growth cycle, but individual K. pneumoniae isolates exhibited a wide range of NR activity levels. The genes of major NR enzymes (nfsA and nfnB) showed a number of sequence variants. Aside from a C-terminal extension of NfnB, which may be responsible for lower NR activity in specific isolates, the genetic differences did not explain the variation in activity. Analysis of important clinical strains (ST11, ST258, ST14 and ST101) showed significant variation in NR activity between isolates within the same sequence type despite conservation of nfsA/nfnB sequences. Addition of methyl viologen (MV), a known activator of soxRS, caused a significant increase in NR activity for all strains, with proportionally larger increases in activity seen for strains with low uninduced NR levels. Real-time PCR on selected strains following exposure to MV showed upregulation of soxS (15–32-fold) and nfsA (5–22-fold) in all strains tested. Expression of nfnB was upregulated 2–5-fold in 4/6 strains tested. High levels of NR activity in the absence of MV activation correlated with nitrofurantoin susceptibility. These data provide evidence that NR gene mutations and regulatory pathways influence NR activity in K. pneumoniae isolates and this is likely to impact treatment efficacy with novel nitro-containing drugs or prodrugs.

AB - To understand the potential utility of novel nitroreductase (NR)-activated prodrugs, NR enzyme activity was assessed in clinical Klebsiella pneumoniae isolates using a NR-activated fluorescent probe. NR activity was constant throughout the bacterial growth cycle, but individual K. pneumoniae isolates exhibited a wide range of NR activity levels. The genes of major NR enzymes (nfsA and nfnB) showed a number of sequence variants. Aside from a C-terminal extension of NfnB, which may be responsible for lower NR activity in specific isolates, the genetic differences did not explain the variation in activity. Analysis of important clinical strains (ST11, ST258, ST14 and ST101) showed significant variation in NR activity between isolates within the same sequence type despite conservation of nfsA/nfnB sequences. Addition of methyl viologen (MV), a known activator of soxRS, caused a significant increase in NR activity for all strains, with proportionally larger increases in activity seen for strains with low uninduced NR levels. Real-time PCR on selected strains following exposure to MV showed upregulation of soxS (15–32-fold) and nfsA (5–22-fold) in all strains tested. Expression of nfnB was upregulated 2–5-fold in 4/6 strains tested. High levels of NR activity in the absence of MV activation correlated with nitrofurantoin susceptibility. These data provide evidence that NR gene mutations and regulatory pathways influence NR activity in K. pneumoniae isolates and this is likely to impact treatment efficacy with novel nitro-containing drugs or prodrugs.

KW - Klebsiella pneumoniae

KW - Methyl viologen

KW - nfsA

KW - Nitroreductase

KW - Prodrug

KW - soxRS

UR - http://www.scopus.com/inward/record.url?scp=85072701010&partnerID=8YFLogxK

U2 - 10.1016/j.ijantimicag.2019.08.009

DO - 10.1016/j.ijantimicag.2019.08.009

M3 - Article

C2 - 31398484

AN - SCOPUS:85072701010

VL - 54

SP - 538

EP - 546

JO - INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS

JF - INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS

SN - 0924-8579

IS - 5

ER -

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