Selective Permeabilization of Gram-Negative Bacterial Membranes Using Multivalent Peptide Constructs for Antibiotic Sensitization
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acsinfecdis.0c00805.pdf
Description
Published version
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5.03 MB
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Author(s)
Chan, Leslie W
Hern, Kelsey E
Ngambenjawong, Chayanon
Lee, Katie
Kwon, Ester J
Hung, Deborah T
Bhatia, Sangeeta N
Date Issued
2021
Journal
ACS Infectious Diseases
Publisher
American Chemical Society (ACS)
Citation
Chan, Leslie W, Hern, Kelsey E, Ngambenjawong, Chayanon, Lee, Katie, Kwon, Ester J et al. 2021. "Selective Permeabilization of Gram-Negative Bacterial Membranes Using Multivalent Peptide Constructs for Antibiotic Sensitization." ACS Infectious Diseases, 7 (4).
Version
Final published version
Abstract
The drug-impermeable bacterial membrane in Gram-negative pathogens limits antibiotic access to intracellular drug targets. To expand our rapidly waning antibiotic arsenal, one approach is to improve the intracellular delivery of drugs with historically poor accumulation in Gram-negative bacteria. To do so, we engineered macromolecular potentiators to permeabilize the Gram-negative membrane to facilitate drug influx. Potentiators, known as WD40, were synthesized by grafting multiple copies of a cationic α-helical antimicrobial peptide, WLBU2, onto a dextran polymer scaffold. WD40 enabled drug uptake in the model pathogen P. aeruginosa, a capability that was not observed with unmodified WLBU2 peptide. WD40 was able to reduce minimum inhibitory concentrations of a drug panel by up to 3 orders of magnitude. Hydrophobic and highly three-dimensional antibiotics exhibited the greatest potentiation. Antibiotic activity was potentiated in several clinical strains and resulted in sensitization of drug-resistant strains to rifampin, a drug not previously used for Gram-negative infections.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
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Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licens
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DOI of Published Version
https://doi.org/10.1021/ACSINFECDIS.0C00805
