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Combined effect of a peptide-morpholino oligonucleotide conjugate and a cell-penetrating peptide as an antibiotic

Donna Wesolowski1, Dulce Alonso, Sidney Altman

  • 1Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520, USA.

Proceedings of the National Academy of Sciences of the United States of America
|May 8, 2013
PubMed

Insights

Improved purification separates cell-penetrating peptide (CPP) from morpholino oligonucleotide (MO) conjugates (PMOs), clarifying their distinct antibiotic effects. The PMO is bacteriocidal, while CPP is bacteriostatic, with combined use enhancing antibiotic activity.

Area of Science:

  • Biochemistry
  • Microbiology
  • Molecular Biology

Background:

  • Cell-penetrating peptide (CPP)-morpholino oligonucleotide (MO) conjugates (PMOs) previously showed antibiotic effects.
  • Earlier preparations contained contaminating free CPPs, leading to both gene-specific and gene-nonspecific effects.

Purpose of the Study:

  • To improve the purification of PMO conjugates.
  • To differentiate the antibiotic mechanisms of PMOs and free CPPs.
  • To confirm the combined antibiotic effects of PMO and CPP.

Main Methods:

  • Developed an improved purification procedure to separate PMO from free CPP and MO.
  • Utilized kinetic analysis to study the effects of PMO and CPP on bacterial viability.
  • Performed mutation assays to assess effects on bacterial viability.

Main Results:

  • The improved purification successfully separated PMO from free CPP and MO.
  • Gene-specific effects were attributed to the PMO, while nonspecific effects resulted from free CPP.
  • Kinetic analysis confirmed that the combined PMO and CPP mixture acts as an antibiotic.
  • CPP demonstrated a bacteriostatic effect, whereas PMO exhibited a bacteriocidal effect.
  • Mutation assays showed no alterations affecting bacterial viability.

Conclusions:

  • The improved purification method allows for the distinct characterization of PMO and CPP antibiotic activities.
  • PMOs possess a bacteriocidal effect, while CPPs have a bacteriostatic effect.
  • The combination of PMO and CPP yields a synergistic antibiotic effect, with potential applications in antimicrobial therapies.
Keywords:
EGS technologyRNase Pgram-negative bacteriagram-positive bacteria

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