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Drug targeting by polyalkylcyanoacrylate nanoparticles is not efficient against persistent Salmonella
M E Page-Clisson1, H Pinto-Alphandary, E Chachaty
1Laboratoire de Pharmacie Galénique et de Biopharmacie, Centre National de la Recherche Scientifique, URA 1218, Université de Paris XI, Châtenay-Malabry, France.
Purpose:
We have investigated the efficacy of colistin and ciprofloxacin, free or bound to polyalkylcyanoacrylate nanoparticles, for the targeting and eradication of Salmonella persisting in the organs of the mononuclear phagocyte system.
Methods:
A model of persistent S. typhimurium infection was developed in C57BL/6 mice using i.v. inoculation of the plasmid-cured strain C53.
Results:
In vivo and ex vivo experiments showed that the persisting bacteria seem to evolve to a nongrowing state during experimental salmonellosis. In vivo treatment with free or nanoparticle-bound colistin did not significantly reduce the number of viable Salmonella C53, either in the liver or the spleen of infected mice. In contrast, in vivo treatment with ciprofloxacin led to a significant decrease of bacterial counts in the liver whatever the stage of infection and the form used. However, none of the treatments were able to sterilize the spleen or the liver. In ex vivo experiments, colistin was only active against bacteria recovered during the early phase of infection, whereas ciprofloxacin exerted its activity at all times postinfection.
Conclusions:
We suggest that the micro-environment in which the bacterial cells persist in vivo probably causes dramatic changes in their susceptibility to antimicrobial agents.
Insights
Ciprofloxacin effectively reduced Salmonella in mouse livers, but neither it nor colistin eradicated bacteria in the spleen or liver. Persistent Salmonella may alter their antimicrobial susceptibility due to their environment.
Area of Science:
- Microbiology
- Pharmacology
- Immunology
Background:
- Persistent Salmonella infections pose challenges in treating organs of the mononuclear phagocyte system.
- Understanding bacterial adaptation during persistent infection is crucial for developing effective therapies.
Purpose of the Study:
- To evaluate the efficacy of colistin and ciprofloxacin, in free and nanoparticle-bound forms, against persistent Salmonella.
- To investigate the impact of nanoparticle delivery on antimicrobial targeting and eradication.
Main Methods:
- A mouse model of persistent Salmonella typhimurium infection was established.
- In vivo and ex vivo experiments were conducted to assess bacterial load reduction.
- Antimicrobial activity of free and nanoparticle-bound colistin and ciprofloxacin was tested.
Main Results:
- Persistent Salmonella in mice adopted a nongrowing state.
- Ciprofloxacin significantly reduced Salmonella in the liver, irrespective of administration form or infection stage.
- Neither colistin nor ciprofloxacin eradicated Salmonella from the spleen or liver; colistin was only effective early in infection.
Conclusions:
- The in vivo micro-environment significantly alters bacterial susceptibility to antimicrobial agents.
- Targeting persistent Salmonella requires strategies that overcome adaptive resistance mechanisms.