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Published on: July 7, 2020
Breaking membrane barriers to neutralize E. coli and K. pneumoniae virulence with PEGylated branched polyethylenimine
Cassandra L Wouters1, Neda Heydarian1, Jennifer Pusavat1
1Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, 101 Stephenson Parkway, Norman, OK 73019, United States of America.
Abstract:
Bacterial infections caused by Gram-negative pathogens, such as those in the family Enterobacteriaceae, are among the most difficult to treat because effective therapeutic options are either very limited or non-existent. This raises serious concern regarding the emergence and spread of multi-drug resistant (MDR) pathogens in the community setting; and thus, creates the need for discovery efforts and/or early-stage development of novel therapies for infections. Our work is directed towards branched polyethylenimine (BPEI) modified with polyethylene glycol (PEG) as a strategy for targeting virulence from Gram-negative bacterial pathogens. Here, we neutralize lipopolysaccharide (LPS) as a barrier to the influx of antibiotics. Data demonstrate that the β-lactam antibiotic oxacillin, generally regarded as ineffective against Gram-negative bacteria, can be potentiated by 600 Da BPEI to kill some Escherichia coli and some Klebsiella pneumoniae. Modification of 600 Da BPEI with polyethylene glycol (PEG) could increase drug safety and improves potentiation activity. The ability to use the Gram-positive agent, oxacillin, against Gram-negative pathogens could expand the capability to deliver effective treatments that simplify, reduce, or eliminate some complicated treatment regimens.
Insights
Novel branched polyethylenimine (BPEI) modified with polyethylene glycol (PEG) can potentiate the antibiotic oxacillin against Gram-negative bacteria. This approach targets lipopolysaccharide (LPS) to overcome multi-drug resistance (MDR) in infections.
Area of Science:
- Microbiology
- Infectious Diseases
- Drug Discovery
Background:
- Gram-negative bacterial infections, particularly those caused by Enterobacteriaceae, pose significant treatment challenges due to limited therapeutic options.
- The rise of multi-drug resistant (MDR) pathogens necessitates the development of novel therapeutic strategies.
Purpose of the Study:
- To investigate branched polyethylenimine (BPEI) modified with polyethylene glycol (PEG) as a novel approach to enhance antibiotic efficacy against Gram-negative pathogens.
- To explore the potential of this modified BPEI to neutralize lipopolysaccharide (LPS) and overcome antibiotic resistance.
Main Methods:
- Synthesis and characterization of BPEI modified with PEG.
- Evaluation of the potentiation activity of modified BPEI on the efficacy of the beta-lactam antibiotic oxacillin against Gram-negative bacteria like Escherichia coli and Klebsiella pneumoniae.
- Assessment of drug safety and improved potentiation activity with PEG modification.
Main Results:
- BPEI (600 Da) demonstrated potentiation of oxacillin against certain strains of Escherichia coli and Klebsiella pneumoniae.
- Modification of BPEI with PEG enhanced drug safety and improved the potentiation activity.
- This strategy enables the use of a Gram-positive agent, oxacillin, against Gram-negative pathogens.
Conclusions:
- Modified BPEI-PEG represents a promising strategy for developing novel therapies against Gram-negative bacterial infections.
- This approach can overcome antibiotic resistance by targeting LPS and expanding treatment options.
- The findings suggest a potential to simplify and improve treatment regimens for complicated infections.
