Selective Permeabilization of Gram-Negative Bacterial Membranes Using Multivalent Peptide Constructs for Antibiotic Sensitization
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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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American Chemical Society (ACS)
2022
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| Online Access: | https://hdl.handle.net/1721.1/142859 |
| _version_ | 1826193985846116352 |
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| author | Chan, Leslie W Hern, Kelsey E Ngambenjawong, Chayanon Lee, Katie Kwon, Ester J Hung, Deborah T Bhatia, Sangeeta N |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Chan, Leslie W Hern, Kelsey E Ngambenjawong, Chayanon Lee, Katie Kwon, Ester J Hung, Deborah T Bhatia, Sangeeta N |
| author_sort | Chan, Leslie W |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T09:48:03Z |
| format | Article |
| id | mit-1721.1/142859 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T09:48:03Z |
| publishDate | 2022 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/1428592024-03-20T18:52:17Z Selective Permeabilization of Gram-Negative Bacterial Membranes Using Multivalent Peptide Constructs for Antibiotic Sensitization Chan, Leslie W Hern, Kelsey E Ngambenjawong, Chayanon Lee, Katie Kwon, Ester J Hung, Deborah T Bhatia, Sangeeta N 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 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. 2022-06-01T19:38:51Z 2022-06-01T19:38:51Z 2021 2022-06-01T19:28:00Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/142859 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). en 10.1021/ACSINFECDIS.0C00805 ACS Infectious Diseases Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licens http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf American Chemical Society (ACS) American Chemical Society |
| spellingShingle | Chan, Leslie W Hern, Kelsey E Ngambenjawong, Chayanon Lee, Katie Kwon, Ester J Hung, Deborah T Bhatia, Sangeeta N Selective Permeabilization of Gram-Negative Bacterial Membranes Using Multivalent Peptide Constructs for Antibiotic Sensitization |
| title | Selective Permeabilization of Gram-Negative Bacterial Membranes Using Multivalent Peptide Constructs for Antibiotic Sensitization |
| title_full | Selective Permeabilization of Gram-Negative Bacterial Membranes Using Multivalent Peptide Constructs for Antibiotic Sensitization |
| title_fullStr | Selective Permeabilization of Gram-Negative Bacterial Membranes Using Multivalent Peptide Constructs for Antibiotic Sensitization |
| title_full_unstemmed | Selective Permeabilization of Gram-Negative Bacterial Membranes Using Multivalent Peptide Constructs for Antibiotic Sensitization |
| title_short | Selective Permeabilization of Gram-Negative Bacterial Membranes Using Multivalent Peptide Constructs for Antibiotic Sensitization |
| title_sort | selective permeabilization of gram negative bacterial membranes using multivalent peptide constructs for antibiotic sensitization |
| url | https://hdl.handle.net/1721.1/142859 |
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