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. 2018 Jun 1:11:835-847.
doi: 10.2147/IDR.S166236. eCollection 2018.

Hybridization and antibiotic synergism as a tool for reducing the cytotoxicity of antimicrobial peptides

Ammar Almaaytah  1 , Mohammed T Qaoud  1 , Ahmad Abualhaijaa  2 , Qosay Al-Balas  3 , Karem H Alzoubi  4
Affiliations

Hybridization and antibiotic synergism as a tool for reducing the cytotoxicity of antimicrobial peptides

Ammar Almaaytah et al. Infect Drug Resist. .

Abstract

Introduction: As the development of new antimicrobial agents faces a historical decline, the issue of bacterial drug resistance has become a serious dilemma that threatens the human population worldwide. Antimicrobial peptides (AMPs) represent an attractive and a promising class of antimicrobial agents.

Aim: The hybridization of AMPs aimed at merging two individual active fragments of native peptides to generate a new AMP with altered physicochemical properties that translate into an enhanced safety profile.

Materials and methods: In this study, we have rationally designed a new hybrid peptide via combining two individual α-helical fragments of both BMAP-27 and OP-145. The resultant peptide, was evaluated for its antimicrobial and antibiofilm activity against a range of microbial strains. The resultant peptide was also evaluated for its toxicity against mammalian cells using hemolytic and anti proliferative assays.

Results: The antimicrobial activity of H4 revealed that the peptide is displaying a broad spectrum of activity against both Gram-positive and Gram-negative bacteria including standard and multidrug-resistant bacterial strains in the range of 2.5-25 μM. The new hybrid peptide displayed potent activity in eradicating biofilm-forming cells, and the reported minimum biofilm eradication concentrations were equal to the minimum inhibitory concentration values reported for planktonic cells. Additionally, H4 exhibited reduced toxicity profiles against eukaryotic cells. Combining H4 peptide with conventional antibiotics has led to a dramatic enhancement of the antimicrobial activity of both agents with synergistic or additive outcomes.

Conclusion: Overall, this study indicates the success of both the hybridization and synergism strategy in developing AMPs as potential antimicrobial therapeutics with reduced toxicity profiles that could be efficiently employed to eradicate resistant bacterial strains and enhance the selectivity and toxicity profiles of native AMPs.

Keywords: antibiotic synergism; antimicrobial peptides; antimicrobial resistance; biofilms; peptide hybridization.

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Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Analytical RP-HPLC chromatogram of the synthetic hybrid peptide H4 displaying a purity of >95%. Abbreviation: RP-HPLC, reverse-phase high-performance liquid chromatography.
Figure 2
Figure 2
Positive ESI-MS analysis of the synthetic peptide H4 showing major peaks in the +4, +5, +6, and +7 charge states of 910.27, 728.38, 607.16, and 520.68 Da, respectively. Abbreviation: ESI-MS, electrospray ionization-mass spectrometry.
Figure 3
Figure 3
Three-dimensional structural modeling of H4. Red regions correspond to helical structures within the peptide, while the green regions represent hinged regions and unordered conformations, respectively. The structure was visualized using Accelrys Discovery Studio software.
Figure 4
Figure 4
Cell survival curves as measured by MTT assay for H4 against two normal mammalian cell lines, Vero and HEK293. Cells were incubated with various concentrations of the peptides, for 24 hours, at 37°C. Control cells represent 100% proliferation, and the mean absorbance of treated cells was related to control values to determine sensitivity. Error bars represent standard error from mean cell proliferation as determined by repeated experiments. Abbreviation: MTT, methylthiazolyldiphenyl-tetrazolium bromide.
See this image and copyright information in PMC

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