Structural dynamics influences the antibacterial activity of a cell-penetrating peptide (KFF)K.

Given the widespread demand for novel antibacterial agents, we modified a cell-penetrating peptide (KFF)K to transform it into an antibacterial peptide. Namely, we inserted a hydrocarbon staple into the (KFF)K sequence to induce and stabilize its membrane-active secondary structure. The staples were introduced at two positions, (KFF)K[5-9] and (KFF)K[2-6], to retain the initial amphipathic character of the unstapled peptide.

Conjugates of Aminoglycosides with Stapled Peptides as a Way to Target Antibiotic-Resistant Bacteria.

The misuse and overuse of antibiotics led to the development of bacterial resistance to existing aminoglycoside (AMG) antibiotics and limited their use. Consequently, there is a growing need to develop effective antimicrobials against multidrug-resistant bacteria. To target resistant strains, we propose to combine 2-deoxystreptamine AMGs, neomycin (NEO) and amikacin (AMK), with a membrane-active antimicrobial peptide anoplin and its hydrocarbon stapled derivative.

Stapled Anoplin as an Antibacterial Agent.

Anoplin is a linear 10-amino acid amphipathic peptide (Gly-Leu-Leu-Lys-Arg-Ile-Lys-Thr-Leu-Leu- ) derived from the venom sac of the solitary wasp. It has broad antimicrobial activity, including an antibacterial one. However, the inhibition of bacterial growth requires several dozen micromolar concentrations of this peptide.