Hansen Anna Mette, Bonke Gitte, Larsen Camilla Josephine, Yavari Niloofar, Nielsen Peter E, Franzyk Henrik
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Panum Institute, University of Copenhagen , Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
Bioconjug Chem. 2016 Apr 20;27(4):863-7. doi: 10.1021/acs.bioconjchem.6b00013. Epub 2016 Mar 10.
Antisense peptide nucleic acid (PNA) oligomers constitute a novel class of potential antibiotics that inhibit bacterial growth via specific knockdown of essential gene expression. However, discovery of efficient, nontoxic delivery vehicles for such PNA oligomers has remained a challenge. In the present study we show that antimicrobial peptides (AMPs) with an intracellular mode of action can be efficient vehicles for bacterial delivery of an antibacterial PNA targeting the essential acpP gene. The results demonstrate that buforin 2-A (BF2-A), drosocin, oncocin 10, Pep-1-K, KLW-9,13-a, (P59→W59)-Tat48-60, BF-2A-RXR, and drosocin-RXR are capable of transporting PNA effectively into E. coli (MICs of 1-4 μM). Importantly, presence of the inner-membrane peptide transporter SbmA was not required for antibacterial activity of PNA-AMP conjugates containing Pep-1-K, KLW-9,13-a, or drosocin-RXR (MICs of 2-4 μM).
反义肽核酸（PNA）寡聚物是一类新型的潜在抗生素，可通过特异性敲低必需基因表达来抑制细菌生长。然而，为这类PNA寡聚物发现高效、无毒的递送载体仍然是一个挑战。在本研究中，我们表明具有细胞内作用模式的抗菌肽（AMPs）可以成为将靶向必需acpP基因的抗菌PNA递送至细菌的有效载体。结果表明，蟾蜍抗菌肽2-A（BF2-A）、果蝇抗菌肽、癌蛋白10、Pep-1-K、KLW-9,13-a、（P59→W59）-Tat48-60、BF-2A-RXR和果蝇抗菌肽-RXR能够有效地将PNA转运到大肠杆菌中（最低抑菌浓度为1-4μM）。重要的是，含有Pep-1-K、KLW-9,13-a或果蝇抗菌肽-RXR的PNA-AMP缀合物的抗菌活性不需要内膜肽转运蛋白SbmA的存在（最低抑菌浓度为2-4μM）。
