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Open AccessArticle

Synthesis and in Silico Modelling of the Potential Dual Mechanistic Activity of Small Cationic Peptides Potentiating the Antibiotic Novobiocin against Susceptible and Multi-Drug Resistant Escherichia coli

1
School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield AL10 9AB, UK
2
UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK
3
NanoPuzzle Medicines Design, Stevenage SG1 2DX, UK
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(23), 9134; https://doi.org/10.3390/ijms21239134
Received: 27 October 2020 / Revised: 24 November 2020 / Accepted: 27 November 2020 / Published: 30 November 2020
(This article belongs to the Section Physical Chemistry and Chemical Physics)
Cationic antimicrobial peptides have attracted interest, both as antimicrobial agents and for their ability to increase cell permeability to potentiate other antibiotics. However, toxicity to mammalian cells and complexity have hindered development for clinical use. We present the design and synthesis of very short cationic peptides (3–9 residues) with potential dual bacterial membrane permeation and efflux pump inhibition functionality. Peptides were designed based upon in silico similarity to known active peptides and efflux pump inhibitors. A number of these peptides potentiate the activity of the antibiotic novobiocin against susceptible Escherichia coli and restore antibiotic activity against a multi-drug resistant E. coli strain, despite having minimal or no intrinsic antimicrobial activity. Molecular modelling studies, via docking studies and short molecular dynamics simulations, indicate two potential mechanisms of potentiating activity; increasing antibiotic cell permeation via complexation with novobiocin to enable self-promoted uptake, and binding the E. coli RND efflux pump. These peptides demonstrate potential for restoring the activity of hydrophobic drugs. View Full-Text
Keywords: antimicrobial peptides; antimicrobial resistance; efflux pump inhibitor; molecular similarity; molecular dynamics; docking; peptide synthesis; antibiotic potentiation antimicrobial peptides; antimicrobial resistance; efflux pump inhibitor; molecular similarity; molecular dynamics; docking; peptide synthesis; antibiotic potentiation
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MDPI and ACS Style

Passarini, I.; Resende, P.E.d.; Soares, S.; Tahmasi, T.; Stapleton, P.; Malkinson, J.; Zloh, M.; Rossiter, S. Synthesis and in Silico Modelling of the Potential Dual Mechanistic Activity of Small Cationic Peptides Potentiating the Antibiotic Novobiocin against Susceptible and Multi-Drug Resistant Escherichia coli. Int. J. Mol. Sci. 2020, 21, 9134. https://doi.org/10.3390/ijms21239134

AMA Style

Passarini I, Resende PEd, Soares S, Tahmasi T, Stapleton P, Malkinson J, Zloh M, Rossiter S. Synthesis and in Silico Modelling of the Potential Dual Mechanistic Activity of Small Cationic Peptides Potentiating the Antibiotic Novobiocin against Susceptible and Multi-Drug Resistant Escherichia coli. International Journal of Molecular Sciences. 2020; 21(23):9134. https://doi.org/10.3390/ijms21239134

Chicago/Turabian Style

Passarini, Ilaria; Resende, Pedro E.d.; Soares, Sarah; Tahmasi, Tadeh; Stapleton, Paul; Malkinson, John; Zloh, Mire; Rossiter, Sharon. 2020. "Synthesis and in Silico Modelling of the Potential Dual Mechanistic Activity of Small Cationic Peptides Potentiating the Antibiotic Novobiocin against Susceptible and Multi-Drug Resistant Escherichia coli" Int. J. Mol. Sci. 21, no. 23: 9134. https://doi.org/10.3390/ijms21239134

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