Multifunctional Antibiotic-Host Defense Peptide Conjugate Kills Bacteria, Eradicates Biofilms, and Modulates the Innate Immune Response

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-1 beta from lipopolysaccharide-stimulated white blood cells. The conjugate demonstrated similar to 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.

Automated summary

A novel vancomycin-innate defense regulator conjugate (V-IDR1018) was developed with multiple functions including bacterial killing, biofilm eradication, and immune modulation. It showed potent antibacterial activity, resistance against antimicrobial resistance, and stimulation of immune responses, making it a valuable candidate for treating complex infectious diseases.