Phosphate-Containing Polyethylene Glycol Polymers Prevent Lethal Sepsis by Multidrug-Resistant Pathogens

Abstract

Antibiotic resistance among highly pathogenic strains of bacteria and fungi is a growing concern in the face of the ability to sustain life during critical illness with advancing medical interventions. The longer patients remain critically ill, the more likely they are to become colonized by multidrug-resistant (MDR) pathogens. The human gastrointestinal tract is the primary site of colonization of many MDR pathogens and is a major source of life-threatening infections due to these microorganisms. Eradication measures to sterilize the gut are difficult if not impossible and carry the risk of further antibiotic resistance. Here, we present a strategy to contain rather than eliminate MDR pathogens by using an agent that interferes with the ability of colonizing pathogens to express virulence in response to hostderived and local environmental factors. The antivirulence agent is a phosphorylated triblock high-molecular-weight polymer (here termed Pi-PEG 15-20) that exploits the known properties of phosphate (P i ) and polyethylene glycol 15-20 (PEG 15-20) to suppress microbial virulence and protect the integrity of the intestinal epithelium. The compound is nonmicrobiocidal and appears to be highly effective when tested both in vitro and in vivo. Structure functional analyses suggest that the hydrophobic bis-aromatic moiety at the polymer center is of particular importance to the biological function of Pi-PEG 15-20, beyond its phosphate content. Animal studies demonstrate that Pi-PEG prevents mortality in mice inoculated with multiple highly virulent pathogenic organisms from hospitalized patients in association with preservation of the core microbiome.

Surviving sepsis campaign: research priorities for sepsis and septic shock

“…Further, microbes alter their virulence in response to both the internal host environment (availability of phosphate) and treatments in critically ill patients (opiates) [223][224][225]. Bacteria in pre-clinical models of sepsis can be tricked into "believing" that the host environment is non-toxic, preventing the development of virulence factors that would ordinarily occur in sepsis, leading to survival advantage in septic rodents [226]. Microbes also possess the capacity for quorum sensing in which individual cells can work together to collectively respond to the environment [227,228].…”

Are gut bacteria associated with the development of anastomotic leaks?

“…The use of non-microbicidal drugs to create microenvironmental conditions that suppress the virulence of pathogens is an attractive strategy to minimize the negative consequences of intestinal microbiome disruption caused by antibiotic use [14,28,29,32,33]. It has been shown previously that phosphate is depleted in the intestinal tract following surgical injury, that this depletion is a major "cue" that triggers bactericidal virulence, and that the maintenance of luminal phosphate abundance in the gut prevents virulence expression [12,14,32,33].…”

“…It has been shown previously that phosphate is depleted in the intestinal tract following surgical injury, that this depletion is a major "cue" that triggers bactericidal virulence, and that the maintenance of luminal phosphate abundance in the gut prevents virulence expression [12,14,32,33]. Since inorganic phosphate is not a suitable agent for phosphate delivery to the site of host-pathogen interaction, because it is readily absorbed in the small intestine, other ways must be found [32].…”

PEGylated lysozymes with anti-septic effects in human endothelial cells and in mice

“…Ackland et al reported that lowmolecular-weight PEG (200e400 Da) reduced inflammatory cytokine expression, pyrexia, and mortality in both LPS and zymosan models of sepsis [17]. Zaborin et al demonstrated that phosphorylated PEG prevents lethal sepsis in mice inoculated with multiple highly virulent pathogenic organisms from hospitalized patients [18]. Based on the biological effect of each LYZ and PEG, we hypothesized that PEGylated LYZ (PEG-LYZ), the combined form of LYZ and PEG, could give synergistic effect on the treatment of sepsis.…”