Healing wounds infected with bacteria requires agents that (1) overcome drug-resistant pathogens, (2) disrupt biofilms, and (3) reduce inflammation from pathogen associated microbial molecules (PAMPS). We show data that one molecule -- 600 Da BPEI that is PEGylated to improve safety -- accomplishes these 3 goals. PEG-BPEI potentiates common antibiotics against drug-resistant Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae. These pathogens both intrinsic and acquired antibiotic resistance, making clinical management of infection a real challenge, particularly when these bacteria are sequestered in biofilms. Against Enterobacteriaceae and their biofilms, the potency of β-lactam antibiotics is restored with 600-Da branched polyethylenimine (600-Da BPEI). Checkerboard assays using microtiter plates demonstrate the potentiation of piperacillin, cefepime, meropenem, imipenem, and erythromycin antibiotics. Growth curves demonstrate that a combination of 600-Da BPEI and piperacillin produces bacteriostatic effects. Scanning electron microscopy (SEM) was used to confirm that the combination treatment leads to abnormal morphology. Data collected with isothermal titration calorimetry and fluorescence spectroscopy demonstrate a mechanism of action in which potentiation at low concentrations of 600-Da BPEI reduces diffusion barriers from lipopolysaccharides without disrupting the outer membrane itself. LPS also stimulates pattern recognition receptors, leading the release of pro-inflammatory cytokines. BPEI and PEG-BPEI bind to LPS to reduce cytokine production. Coupled with the ability to overcome reduce antibiotic activity and biofilms exopolymers, PEG-BPEI provides new opportunities to counter the rise of multidrug-resistant infections.

Universal agent for wounds infected with drug-resistant Pseudomonas aeruginosa and carbapenem-resistant enterobacteriaceae (CRE), including those possessing metallo-beta-lactamases

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.