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
SN - 1661-6596
VL - 21
SP - 1
EP - 19
JO - International Journal of Molecular Sciences (IJMS)
JF - International Journal of Molecular Sciences (IJMS)
IS - 23
M1 - 9134
ER -