| Summary: | Antisense peptide nucleic acids (PNAs) inhibit bacterial growth in several infection models. Since PNAs are not spontaneously taken up by bacteria, they are often conjugated to carriers such as cell-penetrating peptides (CPPs) in order to improve translocation. Hydrophobic counterions such as pyrenebutyrate (PyB) have been shown to facilitate translocation of peptides over natural and artificial membranes. In this study, the capability of PyB to support translocation of CPP-coupled antisense PNAs into bacteria was investigated in <i>Streptococcus pyogenes</i> and <i>Streptococcus pneumoniae</i>. PyB enhanced the antimicrobial activity of CPP-conjugated antisense PNAs in <i>S. pyogenes</i>. The most significant effect of PyB was observed in combination with K8-conjugated anti-<i>gyrA</i> PNAs. In contrast, no significant effect of PyB on the antimicrobial activity of CPP-conjugated PNAs in <i>S. pneumoniae</i> was detected. Uptake of K8-FITC into <i>S. pyogenes</i>, <i>Escherichia coli</i>, and <i>Klebsiella pneumoniae</i> could be improved by pre-incubation with PyB, indicating that PyB supports the antimicrobial effect of CPP-antisense PNAs in <i>S. pyogenes</i> by facilitating the translocation of peptides across the bacterial membrane.
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