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Targeting the disease response with NlpD and LytM for effective non-antibiotic treatment of urinary tract infections

Tran, Hien Thi LU ; Gomes, Inês ; Chaudhuri, Arunima LU orcid ; Nazari, Atefeh LU ; Ahmadi, Shahram LU ; Végh, Hanna LU ; Carneiro, António N B M LU ; Höglund, Urban ; Krintel, Christian LU and Svanborg, Catharina LU , et al. (2026) In The Journal of infectious diseases
Abstract

BACKGROUND: Finding new ways of treating bacterial infections is essential. The NlpD protein, which inhibits RNA Polymerase II (Pol II), has shown therapeutic efficacy against urinary tract infection. This study investigated the mechanism of Pol II inhibition and protection by NlpD and its LytM peptide.

METHODS: Recombinant NlpD and LytM were screened for interactions with constituents of the RNA Polymerase II complex, using AlphaFold predictions and protein interaction technology. Treatment effects were quantified in infected tissues and regulated host response pathways identified by genome-wide transcriptomics analysis in models of acute pyelonephritis and acute cystitis in Irf3-/- and Asc-/- mice, respectively.

RESULTS:... (More)

BACKGROUND: Finding new ways of treating bacterial infections is essential. The NlpD protein, which inhibits RNA Polymerase II (Pol II), has shown therapeutic efficacy against urinary tract infection. This study investigated the mechanism of Pol II inhibition and protection by NlpD and its LytM peptide.

METHODS: Recombinant NlpD and LytM were screened for interactions with constituents of the RNA Polymerase II complex, using AlphaFold predictions and protein interaction technology. Treatment effects were quantified in infected tissues and regulated host response pathways identified by genome-wide transcriptomics analysis in models of acute pyelonephritis and acute cystitis in Irf3-/- and Asc-/- mice, respectively.

RESULTS: LytM was shown to interact with constituents of the Pol II multiprotein complex, inhibiting the CDK12 kinase from phosphorylating the Pol II subunit RPB1 and disrupting Pol II complex formation by interfering with the interaction between PAF1C and RPB1. The protection by LytM against acute pyelonephritis was accompanied by a reduction in gene expression in infected kidneys from >1,900 significantly regulated genes (FC>6) in the placebo group to about 150 in LytM treated mice. The inhibition of gene expression in infected kidneys particularly targeted the excessive innate immune response. A similar effect was observed in acute cystitis. Bacterial clearance was accelerated in both model by LytM treatment, with effects against antibiotic sensitive and resistant Escherichia coli strains.

CONCLUSIONS: The results suggest that inhibiting the disease response of the host, using NlpD or LytM, may offer an efficient alternative to antibiotics in these models.

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publication status
epub
subject
in
The Journal of infectious diseases
publisher
Oxford University Press
external identifiers
  • pmid:42090567
ISSN
1537-6613
DOI
10.1093/infdis/jiag243
language
English
LU publication?
yes
additional info
© The Author(s) 2026. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
id
e5ec381e-7d6e-408f-878a-fafecb889c24
date added to LUP
2026-08-18 15:07:32
date last changed
2026-08-18 15:10:09
@article{e5ec381e-7d6e-408f-878a-fafecb889c24,
  abstract     = {{<p>BACKGROUND: Finding new ways of treating bacterial infections is essential. The NlpD protein, which inhibits RNA Polymerase II (Pol II), has shown therapeutic efficacy against urinary tract infection. This study investigated the mechanism of Pol II inhibition and protection by NlpD and its LytM peptide.</p><p>METHODS: Recombinant NlpD and LytM were screened for interactions with constituents of the RNA Polymerase II complex, using AlphaFold predictions and protein interaction technology. Treatment effects were quantified in infected tissues and regulated host response pathways identified by genome-wide transcriptomics analysis in models of acute pyelonephritis and acute cystitis in Irf3-/- and Asc-/- mice, respectively.</p><p>RESULTS: LytM was shown to interact with constituents of the Pol II multiprotein complex, inhibiting the CDK12 kinase from phosphorylating the Pol II subunit RPB1 and disrupting Pol II complex formation by interfering with the interaction between PAF1C and RPB1. The protection by LytM against acute pyelonephritis was accompanied by a reduction in gene expression in infected kidneys from &gt;1,900 significantly regulated genes (FC&gt;6) in the placebo group to about 150 in LytM treated mice. The inhibition of gene expression in infected kidneys particularly targeted the excessive innate immune response. A similar effect was observed in acute cystitis. Bacterial clearance was accelerated in both model by LytM treatment, with effects against antibiotic sensitive and resistant Escherichia coli strains.</p><p>CONCLUSIONS: The results suggest that inhibiting the disease response of the host, using NlpD or LytM, may offer an efficient alternative to antibiotics in these models.</p>}},
  author       = {{Tran, Hien Thi and Gomes, Inês and Chaudhuri, Arunima and Nazari, Atefeh and Ahmadi, Shahram and Végh, Hanna and Carneiro, António N B M and Höglund, Urban and Krintel, Christian and Svanborg, Catharina and Ambite, Ines}},
  issn         = {{1537-6613}},
  language     = {{eng}},
  month        = {{05}},
  publisher    = {{Oxford University Press}},
  series       = {{The Journal of infectious diseases}},
  title        = {{Targeting the disease response with NlpD and LytM for effective non-antibiotic treatment of urinary tract infections}},
  url          = {{http://dx.doi.org/10.1093/infdis/jiag243}},
  doi          = {{10.1093/infdis/jiag243}},
  year         = {{2026}},
}