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Scientists from IBCh RAS and colleagues clarify the structural basis of thanatin-like antimicrobial peptide activity
Researchers from the Shemyakin-Ovchinnikov Institute of bioorganic chemistry of the Russian Academy of Sciences and their colleagues studied Rip-2, a natural antimicrobial peptide from the bean bug Riptortus pedestris. This β-hairpin peptide is a more active natural homolog of thanatin, a well-known antimicrobial peptide from the predatory stink bug Podisus maculiventris. Such molecules are considered promising antibiotic prototypes against Gram-negative bacteria because they target the Lpt system, which is responsible for lipopolysaccharide transport and outer-membrane formation.
In this study, the authors examined which structural elements of Rip-2 are associated with its enhanced activity compared with thanatin. To this end, they performed phenotypic differential screening of E. coli clones with reduced susceptibility to Rip-2 but retained susceptibility to thanatin, determined minimum inhibitory concentrations for natural and modified peptides, analyzed natural homologs from different Heteroptera species, and carried out structural modeling of the complex with the LptA protein.
All selected clones carried an R76C substitution in LptA, a protein involved in assembly of the Lpt bridge. In these mutants, Rip-2 activity decreased 16-fold, whereas thanatin activity decreased only 2-fold. Additional mutagenesis showed that the C-terminal phenylalanine residue Phe18 makes an important contribution to Rip-2 activity: substitution of this residue weakened the peptide, with aromatic amino acids being better tolerated than non-aromatic ones.
Together, the data allowed the authors to propose a model in which the C-terminal Phe18 residue of Rip-2 contributes to peptide interaction with LptA in the region of Arg76. The findings help clarify which elements of natural thanatin-like peptides determine their activity and may be used in the rational design of new peptide antibiotics. The study was published in International Journal of Molecular Sciences.
october 8