Breaking membrane barriers to neutralize E. coli and K. pneumoniae virulence with PEGylated branched polyethylenimine |
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| Affiliation: | 1. Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, 101 Stephenson Parkway, Norman, OK 73019, United States of America;2. Department of Biology, University of Central Oklahoma, 100 North University Drive, Edmond, OK 73034, United States of America;1. Advanced Research Facilities & Services, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan;2. Department of Molecular Biology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan;3. Laboratory Animal Facilities & Services, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan;4. Department of Anatomy, Ultrastructural Cell Biology, Faculty of Medicine, University of Miyazaki, Miyazaki-City, Miyazaki 889-1692, Japan;5. Laboratory of Genome Stress Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan;1. Université Paris Saclay, Institut de Chimie Physique UMR 8000, CNRS, 91405 Orsay Cedex, France;2. Laboratory of Applied Biotechnology (LBA3B), AZM Center for Research in Biotechnology and its Applications, Doctoral School for Sciences and Technology, Lebanese University, Tripoli 1300, Lebanon;3. Univ. Bordeaux, Bordeaux INP, CNRS, ISM, UMR 5255, F-33402 Talence, France;4. Univ. Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248, F-33600 Pessac, France;1. Department of Neurobiology, Key Laboratory of Human Functional Genomics of Jiangsu Province, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China;2. Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China;3. Child Mental Health Research Center, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu, China;4. Institute for Stem Cell and Neural Regeneration, State Key Laboratory of Reproductive Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, China;1. National Institute of Science Education and Research Bhubaneswar, School of Biological Sciences, P.O. Jatni, Khurda 752050, Odisha, India;2. Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400094, India |
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| 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. |
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