Selective Permeabilization of Gram-Negative Bacterial Membranes Using Multivalent Peptide Constructs for Antibiotic Sensitization
| Autor: | Chan, Leslie W, Hern, Kelsey E, Ngambenjawong, Chayanon, Lee, Katie, Kwon, Ester J, Hung, Deborah T, Bhatia, Sangeeta N |
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| Rok vydání: | 2021 |
| Předmět: |
drug resistance
Prevention Microbial Sensitivity Tests Anti-Bacterial Agents Vaccine Related antimicrobial peptides antibiotic adjuvant Infectious Diseases Emerging Infectious Diseases antibiotic potentiator 5.1 Pharmaceuticals Medical Microbiology Gram-negative bacteria Biodefense Gram-Negative Bacteria 2.2 Factors relating to the physical environment Antimicrobial Resistance Rifampin multivalent Aetiology Development of treatments and therapeutic interventions Infection Biotechnology |
| Zdroj: | ACS infectious diseases, vol 7, iss 4 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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