jfura210

Incorporation of silicon-containing amino acids in peptides is known to endow the peptide with desirable properties such as improved proteolytic stability and increased lipophilicity. In the presented study, we demonstrate that incorporation of β-silicon-β3-amino acids into the antimicrobial peptide alamethicin provides the peptide with improved membrane permeabilizing properties. A robust synthetic procedure for the construction of β-silicon-β3-amino acids was developed and the amino acid analogues were incorporated into alamethicin at different positions of the hydrophobic face of the amphipathic helix by using SPPS. The incorporation was shown to provide up to 20-fold increase in calcein release as compared with wild-type alamethicin.

Permeabilized by silicon: Incorporation of β-silicon-β3-amino acids into the antimicrobial peptide alamethicin improves the membrane permeabilizing action of the peptide. A synthetic procedure to access β-silicon-β3-amino acids was developed and the amino acid analogues were incorporated into alamethicin at different positions (see scheme). The overall lipophilicity of the peptide was improved, resulting in a 20-fold increase in calcein release as compared with wild-type alamethicin.

Conventional antibiotics are ineffective against non-replicating bacteria (for example, bacteria within biofilms). We report a series of halogenated phenazines (HP), inspired by marine antibiotic 1, that targets persistent bacteria. HP 14 demonstrated the most potent biofilm eradication activities to date against MRSA, MRSE, and VRE biofilms (MBEC=0.2–12.5 μM), as well as the effective killing of MRSA persister cells in non-biofilm cultures. Frontline MRSA treatments, vancomycin and daptomycin, were unable to eradicate MRSA biofilms or non-biofilm persisters alongside 14. HP 13 displayed potent antibacterial activity against slow-growing M. tuberculosis (MIC=3.13 μM), the leading cause of death by bacterial infection around the world. HP analogues effectively target persistent bacteria through a mechanism that is non-toxic to mammalian cells and could have a significant impact on treatments for chronic bacterial infections.

Killing the quiet bacteria: Biofilms and quiescent persister cells are typically resistant to standard antibiotics, and contribute to many human infections. Halogenated phenazines based on a marine natural product are shown to be potent anti-biofilm and anti-persister cell compounds, while displaying very limited cytotoxicity in mammalian cells.