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Front. Microbiol. | doi: 10.3389/fmicb.2019.01032

PNA length restriction of antibacterial activity of peptide-PNA conjugates in Escherichia coli through effects of the inner membrane

 Lise Goltermann1, Niloofar Yavari1, meiqin Zhang1 and  Peter E. Nielsen1*
  • 1University of Copenhagen, Denmark

Peptide Nucleic Acid (PNA)-peptide conjugates targeting essential bacterial genes are showing promise as antisense antimicrobials in drug discovery. Optimization has focused on selection of target genes and exact localization around the ribosome binding site, but surprisingly a length optimum around 10-12 nucleobases has been found. Addressing this observation, we have investigated the relationship between PNA-length, PNA-RNA duplex stability and antimicrobial activity in E. coli in more detail. For PNAs of identical length of ten nucleobases the expected reverse correlation between the thermal stability (Tm) of the PNA-RNA duplex and the MIC for single mismatched PNAs was found. Also the expected direct correlation between the length of the PNA and the PNA-RNA duplex stability was found. Nonetheless, 10-mer PNAs (in a 6-18 mer extension series of (KFF)3K- and (RXR)4 conjugates) were the most active as antisense antimicrobials in both wild type E.coli MG1655 and AS19 , suggesting that the size constraint is related to the bacterial uptake of PNA-peptide conjugates. This conclusion was supported by flow cytometry data showing higher bacterial uptake of shorter PNA fluorophore labeled conjugates . Interestingly, the size-limited uptake seems independent on outer membrane integrity (AS19), and thus the results suggest that inner membrane limits the molecular size for peptide-PNA passage.

Keywords: antibiotic, antisense, Peptide nucleic acid ( PNA ), peptide conjugate, Cellular uptake, Escherichia coli

Received: 08 Feb 2019; Accepted: 24 Apr 2019.

Edited by:

Steven L. Cobb, Durham University, United Kingdom

Reviewed by:

Alfonso SOLER-BISTUE, CONICET Institute of Biotechnological Research (IIB-INTECH), Argentina
Brett Mellbye, Oregon State University, United States  

Copyright: © 2019 Goltermann, Yavari, Zhang and Nielsen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Peter E. Nielsen, University of Copenhagen, Copenhagen, 1017, Capital Region of Denmark, Denmark, ptrn@sund.ku.dk