Phosphate-containing polyethylene glycol polymers prevent lethal sepsis by multidrug-resistant pathogens

Area of Science:

• Microbiology
• Polymer Science
• Critical Care Medicine

Background:

• Antibiotic resistance in pathogenic bacteria and fungi is a growing global health concern.
• Multidrug-resistant (MDR) pathogens frequently colonize the gastrointestinal tract of critically ill patients, leading to life-threatening infections.
• Current gut sterilization methods are often ineffective and risk exacerbating antibiotic resistance.

Purpose of the Study:

• To introduce a novel strategy for managing MDR pathogens by containing them rather than eliminating them.
• To investigate the efficacy of a phosphorylated triblock high-molecular-weight polymer (Pi-PEG 15-20) as an antivirulence agent.
• To assess the compound's ability to suppress pathogen virulence and protect intestinal epithelial integrity.

Main Methods:

• Development and characterization of Pi-PEG 15-20, a polymer designed to interfere with pathogen virulence factor expression.
• In vitro and in vivo testing of Pi-PEG 15-20's efficacy against MDR pathogens.
• Structure-function analysis to identify key components of the polymer responsible for its biological activity.
• Animal studies using mice challenged with virulent pathogens to evaluate mortality and microbiome preservation.

Main Results:

• Pi-PEG 15-20 effectively suppresses the virulence of colonizing MDR pathogens without being microbiocidal.
• The compound demonstrates efficacy in both in vitro and in vivo experimental models.
• Structure-function studies highlight the importance of the polymer's hydrophobic bis-aromatic moiety for its biological activity.
• In vivo studies showed Pi-PEG 15-20 prevented mortality in mice infected with virulent pathogens and preserved the gut microbiome.

Conclusions:

• Pi-PEG 15-20 represents a promising antivirulence strategy for managing MDR pathogen colonization in critically ill patients.
• This non-microbiocidal approach offers a potential alternative to traditional antibiotics, mitigating the risk of further resistance.
• The preservation of the host microbiome alongside virulence suppression is a key advantage of this novel therapeutic agent.