Critical Side Chain Effects of Cell-Penetrating Peptides for Transporting Oligo Peptide Nucleic Acids in Bacteria

Of various methods for delivering functional molecules into cells, a chemical approach using cell-penetrating peptides (CPPs) is facile and highly efficient. Currently, however, there are few examples of CPPs highly efficient with bacteria in contrast to CPPs targeting animal cells, and thus our understanding of the structural effects of these bacteria-efficient CPPs, termed as BCPPs, on permeation efficiency is limited. Herein, we report a comprehensive investigation on the permeation efficiencies of cationic short peptides through bacterial cell membranes. We observed that elongating the length of the main chain increased permeation efficiency. More interestingly, the length of the peptide side chain critically affected permeation efficiency; shortening the side chain significantly enhanced efficiency. Among the BCPPs investigated, 2,3-diaminopropionic acid nonamer showed the highest permeation efficiency into bacterial cells of diverse strains, allowing the transport of oligo peptide nucleic acids and subsequent growth inhibition. This study provides insights into the molecular design of efficient BCPPs for manipulating bacterial growth.