High efficacytreatment of murine Pseudomonas aeruginosa catheter-associated urinary tract infections using the c-di-GMP modulating anti-biofilmcompound Disperazol in combination with ciprofloxacin

Louise Dahl Hultqvist, Jens Bo Andersen, Carl Martin Nilsson, Charlotte Uldahl Jansen, Morten Rybtke, Tim Holm Jakobsen, Thomas Eiland Nielsen, Klaus Qvortrup, Claus Moser, Michael Graz, Katrine Qvortrup, Tim Tolker-Nielsen*, Michael Givskov

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

1 Citation (Scopus)

Abstract

Persistent urinary tract infections (UTIs) in hospitalized patients constitute an important medical problem. It is estimated that 75% of nosocomial UTIs are associated with urinary tract catheters with P. aeruginosa being a species that forms biofilmson these catheters. These infections are highly resistant to standard-of-care antibiotics, and the effectsof the host immune defenses, which allows for development of persistent infections. With antibiotics losing their efficacy,new treatment options against resilient infections, such as catheter-associated urinary tract infections (CAUTIs), are critically needed. Central to our anti-biofilmapproach is the manipulation of the c-di-GMP signaling pathway in P. aeruginosa to switch bacteria from the protective biofilmto the unprotected planktonic mode of life. We recently identifieda compound (H6-335-P1), that stimulates the c-di-GMP degrading activity of the P. aeruginosa BifA protein which plummets the intracellular c-di-GMP content and induces dispersal of P. aeruginosa biofilmbacteria into the planktonic state. In the present study, we formulated H6-335-P1 as a hydrochloride salt (Disperazol), which is water-soluble and facilitates delivery via injection or oral administration. Disperazol can work as a monotherapy, but we observed a 100-fold improvement in efficacywhen treating murine P. aeruginosa CAUTIs with a Disperazol/ciprofloxacincombination. Biologically active Disperazol reached the bladder 30 min after oral administration. Our study provides proof of concept that Disperazol can be used in combination with a relevant antibiotic for effectivetreatment of CAUTIs.

Original languageEnglish
Article numbere01481-23
JournalAntimicrobial Agents and Chemotherapy
Volume68
Issue number6
Number of pages16
ISSN0066-4804
DOIs
Publication statusPublished - 2024

Bibliographical note

Publisher Copyright:
© 2024 American Society for Microbiology.

Keywords

  • anti-biofilmcompound
  • antibiotic resistance (AMR)
  • biofilm,infection
  • c-di-GMP regulation
  • CAUTI
  • Pseudomonas aeruginosa

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