A range of new water-compatible optically pure metallohelices - made by self-assembly of simple non-peptidic organic components around Fe ions - exhibit similar architecture to some natural cationic antimicrobial peptides (CAMPs) and are found to have high, structure-dependent activity against bacteria, including clinically problematic Gram-negative pathogens. A key compound is shown to freely enter rapidly dividing E. coli cells without significant membrane disruption, and localise in distinct foci near the poles. Several related observations of CAMP-like mechanisms are made via biophysical measurements, whole genome sequencing of tolerance mutants and transcriptomic analysis. These include: high selectivity for binding of G-quadruplex DNA over double stranded DNA; inhibition of both DNA gyrase and topoisomerase I in vitro; curing of a plasmid that contributes to the very high virulence of the E. coli strain used; activation of various two-component sensor/regulator and acid response pathways; and subsequent attempts by the cell to lower the net negative charge of the surface. This impact of the compound on multiple structures and pathways corresponds with our inability to isolate fully resistant mutant strains, and supports the idea that CAMP-inspired chemical scaffolds are a realistic approach for antimicrobial drug discovery, without the practical barriers to development that are associated with natural CAMPS.

• Publikační typ
• časopisecké články MeSH

We have investigated structural changes of peptides related to antimicrobial peptide Halictine-1 (HAL-1) induced by interaction with various membrane-mimicking models with the aim to identify a mechanism of the peptide mode of action and to find a correlation between changes of primary/secondary structure and biological activity. Modifications in the HAL-1 amino acid sequence at particular positions, causing an increase of amphipathicity (Arg/Lys exchange), restricted mobility (insertion of Pro) and consequent changes in antimicrobial and hemolytic activity, led to different behavior towards model membranes. Secondary structure changes induced by peptide-membrane interaction were studied by circular dichroism, infrared spectroscopy, and fluorescence spectroscopy. The experimental results were complemented by molecular dynamics calculations. An α-helical structure has been found to be necessary but not completely sufficient for the HAL-1 peptides antimicrobial action. The role of alternative conformations (such as β-sheet, PPII or 310-helix) also seems to be important. A mechanism of the peptide mode of action probably involves formation of peptide assemblies (possibly membrane pores), which disrupt bacterial membrane and, consequently, allow membrane penetration.

• Klíčová slova
• antibacterial peptides, circular dichroism, fluorescence, halictine, infrared spectroscopy,
• MeSH
• antibakteriální látky chemie   metabolismus   MeSH
• fosfatidylcholiny chemie   MeSH
• fosfatidylglyceroly chemie   MeSH
• hydrofobní a hydrofilní interakce MeSH
• kationické antimikrobiální peptidy chemie   metabolismus   MeSH
• kinetika MeSH
• konformace proteinů, alfa-helix MeSH
• konformace proteinů, beta-řetězec MeSH
• lipidové dvojvrstvy chemie   MeSH
• permeabilita MeSH
• sekvence aminokyselin MeSH
• simulace molekulární dynamiky MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky MeSH
• fosfatidylcholiny MeSH
• fosfatidylglyceroly MeSH
• kationické antimikrobiální peptidy MeSH
• lipidové dvojvrstvy MeSH