Proline-rich antimicrobial peptides (PrAMPs) are promising
candidates for the treatment of infections caused by highpriority
human pathogens. Their mode of action consists of (I)
passive diffusion across the outer membrane, (II) active transport
through the inner membrane, and (III) inhibition of protein
biosynthesis by blocking the exit tunnel of the 70S ribosome.
We tested whether in vitro data on ribosomal binding and
bacterial uptake could predict the antibacterial activity of
PrAMPs against Gram-negative and Gram-positive bacteria.
Ribosomal binding and bacterial uptake rates were measured
for 47 derivatives of PrAMP Onc112 and compared to the
minimal inhibitory concentrations (MIC) of each peptide.
Ribosomal binding was evaluated for ribosome extracts from
four Gram-negative bacteria. Bacterial uptake was assessed by
quantifying each peptide in the supernatants of bacterial
cultures. Oncocin analogues with a higher net positive charge
appeared to be more active, although their ribosome binding
and uptake rates were not necessarily better than for Onc112.
The data suggest a complex mode of action influenced by
further factors improving or reducing the antibacterial activity,
including diffusion through membranes, transport mechanism,
secondary targets, off-target binding, intracellular distribution,
and membrane effects. Relying only on in vitro binding and
uptake data may not be sufficient for the rational development
of more active analogues.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:86804 |
| Date | 10 August 2023 |
| Creators | Kolano, Lisa, Knappe, Daniel, Berg, Angela, Berg, Thorsten, Hoffmann, Ralf |
| Publisher | Wiley-VCH |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | e202100609, 10.1002/cbic.202100609 |
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