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. 2016 May 9;17(5):1854-9.
doi: 10.1021/acs.biomac.6b00286. Epub 2016 Apr 13.

Helical 1:1 α/Sulfono-γ-AA Heterogeneous Peptides with Antibacterial Activity

Fengyu She  1 , Alekhya Nimmagadda  1 , Peng Teng  1 , Ma Su  1 , Xiaobing Zuo  2 , Jianfeng Cai  1
Affiliations

Helical 1:1 α/Sulfono-γ-AA Heterogeneous Peptides with Antibacterial Activity

Fengyu She et al. Biomacromolecules. .

Abstract

As one of the greatest threats facing the 21st century, antibiotic resistance is now a major public health concern. Host-defense peptides (HDPs) offer an alternative approach to combat emerging multi-drug-resistant bacteria. It is known that helical HDPs such as magainin 2 and its analogs adopt cationic amphipathic conformations upon interaction with bacterial membranes, leading to membrane disruption and subsequent bacterial cell death. We have previously shown that amphipathic sulfono-γ-AApeptides could mimic magainin 2 and exhibit bactericidal activity. In this article, we demonstrate for the first time that amphipathic helical 1:1 α/sulfono-γ-AA heterogeneous peptides, in which regular amino acids and sulfono-γ-AApeptide building blocks are alternatively present in a 1:1 pattern, display potent antibacterial activity against both Gram-positive and Gram-negative bacterial pathogens. Small angle X-ray scattering (SAXS) suggests that the lead sequences adopt defined helical structures. The subsequent studies including fluorescence microscopy and time-kill experiments indicate that these hybrid peptides exert antimicrobial activity by mimicking the mechanism of HDPs. Our findings may lead to the development of HDP-mimicking antimicrobial peptidomimetics that combat drug-resistant bacterial pathogens. In addition, our results also demonstrate the effective design of a new class of helical foldamer, which could be employed to interrogate other important biological targets such as protein-protein interactions in the future.

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Conflict of interest statement

Notes

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
General chemical structures of α-peptide, sulfono-γ-AApeptide, and 1:1 α/sulfono-γ-AA peptide.
Figure 2
Figure 2
Schematic representation of the helical 1:1 α/sulfono-γ-AA heterogeneous peptides. The numbers represent the position of the residue in a sequence. a and b denote the chiral side chain and the sulfonamido side chain from a sulfono-γ-AA building block, respectively.
Figure 3
Figure 3
Structures of antimicrobial 1:1 α/sulfono-γ-AA heterogeneous peptides. In order to illustrate their cationic charge (colored in blue) and hydrophobic group (colored in red) distribution, the sequences are schematically shown on the helical scaffold.
Figure 4
Figure 4
Krakty plot of 1, 3, 4, 5, and 6 measured in pH 7.4 PBS buffer. The peak around 0.1 Å−1 and the minimum in the q range of 0.2–0.4 Å−1 suggest 3 (red), 4 (blue), 5 (green), and 6 (magenta) form well-defined helical structures.
Figure 5
Figure 5
Fluorescence micrographs of S. aureus that are treated or not treated with 10 μg/mL 1:1 α/sulfono-γ-AA peptide 6 for 2 h: (a1) control, no treatment, DAPI stained; (a2) control, no treatment, PI stained; (b1) treatment with 6, DAPI stained; (b2) treatment with 6, PI stained.
Figure 6
Figure 6
Time-kill curves of 6 for MRSA. The killing activity was monitored for the first 2 h. The concentrations were 4× MIC, 8× MIC, and 16× MIC, respectively.
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