In silico Analysis of Native Cyclotides with Antibacterial Activity against Gram-negative Bacteria

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Abstract
There is an ongoing search for new alternatives to antibiotics because of the fast evolving pathogenic bacterial strains which are resistant to the existing antibiotics. Plant-based cyclotides have been shown to posses diverse bioactivities including potent antibacterial activity. Cyclotides are extremely stable cyclic peptides of 27–37 amino acids which are highly resistant against thermal, chemical and enzymatic degradation. Keeping in view the potential of cyclotides as antibacterial agents, an in silico analysis of native cyclotides, screened against Gram-negative bacteria was undertaken. Cyclotides with minimum inhibitory concentration (MIC) less than 10 μM and more than 10 μM were considered potent and non-potent, respectively. The amino acid composition/properties (viz. number of basic residues, average charge, isoelectric point) were significantly higher in potent antibacterial cyclotides compared to non-potent cyclotides. Two potent antibacterial cyclotides (circulin B and cyclopsychotride A) with low hemolytic activity were compared to non-potent cyclotide (tricyclon A) at the structural level. Surface models of potent cyclotides revealed a hydrophobic patch with larger number of residues compared to non-potent cyclotide. Studies using PPM server showed higher stability of potent cyclotides during peptide-membrane interaction as indicated by lower ΔGtransfer and lower tilt angle along with higher penetration depth compared to the higher ΔGtransfer and tilt angle with lower penetration depth in non-potent cyclotide, tricyclon A. Molecular dynamics simulations further confirmed the results of cyclotide-membrane interaction, obtained using PPM server. Hence, in silico studies can reveal the potential of the potent cyclotides as antibacterial agents that can be explored further for application in pharmaceutics. Similar studies can also be extended to assess other newly discovered native cyclotides for their potential applications as antibacterial agents.

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