TY - JOUR
T1 - High efficacytreatment of murine Pseudomonas aeruginosa catheter-associated urinary tract infections using the c-di-GMP modulating anti-biofilmcompound Disperazol in combination with ciprofloxacin
AU - Hultqvist, Louise Dahl
AU - Andersen, Jens Bo
AU - Nilsson, Carl Martin
AU - Jansen, Charlotte Uldahl
AU - Rybtke, Morten
AU - Jakobsen, Tim Holm
AU - Nielsen, Thomas Eiland
AU - Qvortrup, Klaus
AU - Moser, Claus
AU - Graz, Michael
AU - Qvortrup, Katrine
AU - Tolker-Nielsen, Tim
AU - Givskov, Michael
N1 - Publisher Copyright:
© 2024 American Society for Microbiology.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - anti-biofilmcompound
KW - antibiotic resistance (AMR)
KW - biofilm,infection
KW - c-di-GMP regulation
KW - CAUTI
KW - Pseudomonas aeruginosa
U2 - 10.1128/aac.01481-23
DO - 10.1128/aac.01481-23
M3 - Journal article
C2 - 38717093
AN - SCOPUS:85195173730
VL - 68
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 6
M1 - e01481-23
ER -