Multifunctional Antibiotic-Host Defense Peptide Conjugate Kills Bacteria, Eradicates Biofilms, and Modulates the Innate Immune Response
| Autor: | Robert E. W. Hancock, Noushin Akhoundsadegh, Morgan A. Alford, Hashem Etayash, Matthew Drayton, Suzana K. Straus |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Methicillin-Resistant Staphylococcus aureus
Chemokine Multidrug tolerance medicine.drug_class Antibiotics Microbial Sensitivity Tests Microbiology 03 medical and health sciences In vivo Staphylococcus epidermidis Drug Discovery medicine Humans 030304 developmental biology 0303 health sciences Innate immune system biology Bacteria 030306 microbiology Chemistry Biofilm biology.organism_classification Immunity Innate 3. Good health Anti-Bacterial Agents Biofilms biology.protein Molecular Medicine Conjugate Antimicrobial Cationic Peptides |
| Zdroj: | Journal of medicinal chemistry. 64(22) |
| ISSN: | 1520-4804 |
| Popis: | Effective anti-infective therapies are required to offset the rise in antibiotic resistance. A novel vancomycin-innate defense regulator conjugate (V-IDR1018) was constructed with multimodal functionality, including bacterial killing, biofilm eradication, and immune modulation. The conjugate killed bacteria within 30 min, exhibited potent activity against persister cells, and showed no susceptibility to antimicrobial resistance in tissue culture assays. Additionally, it stimulated the release of chemokine MCP-1 and anti-inflammatory cytokine IL-10 and suppressed pro-inflammatory IL-1β from lipopolysaccharide-stimulated white blood cells. The conjugate demonstrated ∼90% eradication efficacy when assessed against the MRSA biofilm formed on an organoid human skin equivalent. Similarly, when evaluated in a murine, high-density skin abscess infection model using MRSA or Staphylococcus epidermidis, the conjugate decreased dermonecrosis and reduced bacterial load. The exceptional in vitro and in vivo efficacy of the conjugate, in addition to its safety profile, makes it a valuable candidate to treat complex infectious diseases. |
| Databáze: | OpenAIRE |
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