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Peptido-mimetic Approach in the Design of Syndiotactic Antimicrobial Peptides

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Abstract

Biocompatibility, low toxicity and high selectivity towards bacterial cells has been the hallmark of peptide-based antibiotics. The innate immune system has been employing such molecular systems against invading pathogens as a successful defense strategy. In this study, we attempt to develop topologically constrained antimicrobial peptides with syndiotactic stereochemical arrangement, by incorporating L and D amino acids successively in its amino acid sequence. Acetylated versions of the designed peptides were also examined for its influence on bactericidal potency, against Gram-positive and Gram-negative bacteria. Syndiotactic stereochemical arrangement of the polypeptide main chain mimics stereochemistry of Gramicidin, a naturally occurring antimicrobial peptides. Gramicidin is a class of penta-deca-peptides isolated from soil bacteria Bacillus brevis, but their utility as antibiotic was limited to topical use due to high levels of hemotoxicity. Activity profiles of the four de novo designed peptide variants show higher specificity towards Gram-positive bacteria than Gram-negative variants, matching earlier reports on the therapeutic potential of gramicidin as a broad spectrum antibiotic. Significantly, our hemolytic assay confirms very low (<1%) levels of toxicity for the designed peptides unlike gramicidin. Earlier reports confirm that incorporation of D amino acids effectively negates the possibility of proteolytic degradation, thus pointing to the potential utility of de novo designed peptides with diversified stereochemistry as a promising new approach in the generation of novel antibiotic peptides.

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Abbreviations

MD:

Molecular dynamics

RMSD:

Root mean square deviation

Rg:

Radius of gyration

FE-SEM:

Field emission scanning electron microscopy

MS:

Mass spectrometry

CFU:

Colony forming unit

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Acknowledgements

Authors acknowledge Central Instrument Facility IIT Guwahati, Ms. Sajitha Sashidharan, Ms. Ruchika Goyal for their contributions in this manuscript.

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Authors and Affiliations

  1. Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam, 781039, India

    Prakash Kishore Hazam, Gaurav Jerath, Nitin Chaudhary & Vibin Ramakrishnan

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  1. Prakash Kishore Hazam
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  2. Gaurav Jerath
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  3. Nitin Chaudhary
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  4. Vibin Ramakrishnan
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Correspondence to Vibin Ramakrishnan.

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Funding Sources

This study was jointly funded by Department of Biotechnology, Govt. of India (Grant No. BT/350/NE/TBP/2012) and Indian Institute of Technology Guwahati, India.

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Hazam, P.K., Jerath, G., Chaudhary, N. et al. Peptido-mimetic Approach in the Design of Syndiotactic Antimicrobial Peptides. Int J Pept Res Ther 24, 299–307 (2018). https://doi.org/10.1007/s10989-017-9615-3

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