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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. / Passarini, Ilaria; Ernesto de Resende, Pedro; Soares, Sarah; Tahmasi, Tadeh; Stapleton, Paul; Malkinson, John; Zloh, Mire; Rossiter, Sharon.

In: International Journal of Molecular Sciences, Vol. 21, No. 23, 9134, 30.11.2020, p. 1-19.

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@article{852f41e8fd434d6e8fd2c65e1fc83827,
title = "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",
abstract = "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.",
keywords = "Antibiotic potentiation, Antimicrobial peptides, Antimicrobial resistance, Docking, Efflux pump inhibitor, Molecular dynamics, Molecular similarity, Peptide synthesis",
author = "Ilaria Passarini and {Ernesto de Resende}, Pedro and Sarah Soares and Tadeh Tahmasi and Paul Stapleton and John Malkinson and Mire Zloh and Sharon Rossiter",
note = "Funding Information: Funding: Tadeh Tahmasi was partially supported by a Wellcome Vacation Scholarship (202526/Z/16/Z). Pedro de Resende and Sarah Soares were supported by CAPES‐Brazil (Coordena{\c c}{\~a}o de Aperfei{\c c}oamento de Pessoal de N{\'i}vel Superior). Funding Information: Acknowledgments: Ilaria Passarini was supported by a University of Hertfordshire PhD studentship. Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland. ",
year = "2020",
month = nov,
day = "30",
doi = "10.3390/ijms21239134",
language = "English",
volume = "21",
pages = "1--19",
journal = "International Journal of Molecular Sciences",
issn = "1422-0067",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "23",

}

RIS

TY - JOUR

T1 - 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

AU - Passarini, Ilaria

AU - Ernesto de Resende, Pedro

AU - Soares, Sarah

AU - Tahmasi, Tadeh

AU - Stapleton, Paul

AU - Malkinson, John

AU - Zloh, Mire

AU - Rossiter, Sharon

N1 - Funding Information: Funding: Tadeh Tahmasi was partially supported by a Wellcome Vacation Scholarship (202526/Z/16/Z). Pedro de Resende and Sarah Soares were supported by CAPES‐Brazil (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior). Funding Information: Acknowledgments: Ilaria Passarini was supported by a University of Hertfordshire PhD studentship. Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2020/11/30

Y1 - 2020/11/30

N2 - 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.

AB - 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.

KW - Antibiotic potentiation

KW - Antimicrobial peptides

KW - Antimicrobial resistance

KW - Docking

KW - Efflux pump inhibitor

KW - Molecular dynamics

KW - Molecular similarity

KW - Peptide synthesis

UR - http://www.scopus.com/inward/record.url?scp=85096976541&partnerID=8YFLogxK

U2 - 10.3390/ijms21239134

DO - 10.3390/ijms21239134

M3 - Article

C2 - 33266278

VL - 21

SP - 1

EP - 19

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1422-0067

IS - 23

M1 - 9134

ER -