Antimicrobial synergy between mRNA targeted peptide nucleic acid and antibiotics in E. coli

Jaime I Castillo; Marcin Równicki; Monika Wojciechowska; Joanna Trylska

doi:10.1016/j.bmcl.2018.07.037

Antimicrobial synergy between mRNA targeted peptide nucleic acid and antibiotics in E. coli

Bioorg Med Chem Lett. 2018 Oct 1;28(18):3094-3098. doi: 10.1016/j.bmcl.2018.07.037. Epub 2018 Jul 27.

Authors

Jaime I Castillo¹, Marcin Równicki², Monika Wojciechowska³, Joanna Trylska⁴

Affiliations

¹ Centre of New Technologies, University of Warsaw, S. Banacha 2c, 02-097 Warsaw, Poland; Instituto Tecnológico y de Estudios Superiores de Monterey, Campus Monterrey, Eugenio Garza Sada 2501, 64849 Monterrey, N.L., Mexico.
² Centre of New Technologies, University of Warsaw, S. Banacha 2c, 02-097 Warsaw, Poland; College of Inter-Faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, S. Banacha 2c, 02-097 Warsaw, Poland.
³ Centre of New Technologies, University of Warsaw, S. Banacha 2c, 02-097 Warsaw, Poland.
⁴ Centre of New Technologies, University of Warsaw, S. Banacha 2c, 02-097 Warsaw, Poland. Electronic address: [email protected].

PMID: 30082123
DOI: 10.1016/j.bmcl.2018.07.037

Abstract

A combination of antibacterial agents should make the emergence of resistance in bacteria less probable. Thus we have analyzed the synergistic effects between antibacterial antisense peptide nucleic acids (PNA) and conventional antibiotics against Escherichia coli AS19 (lipopolysaccharide defective) strain and a derivative of a pathogenic strain E. coli O157:H7. PNAs were designed to target mRNA transcripts encoding the essential acyl carrier protein (gene acpP) and conjugated to the cell-penetrating peptide (KFF)₃K for cellular uptake. Antibiotics included aminoglycosides, aminopenicillins, polymyxins, rifamycins, sulfonamides and trimethoprim. Synergies were evaluated using the checkerboard technique. Fractional Inhibitory Concentration indices (FICi) were calculated for all combinations based on the minimal inhibitory concentration of each individual agent. The results demonstrate two novel synergistic combinations of antimicrobial agents, namely, (KFF)₃K-PNA anti-acpP with polymyxin B and (KFF)₃K-PNA anti-acpP with trimethoprim (both with FICi = 0.38). Polymyxin B's synergy postulates cell wall targeted antibiotics as attractive agents to improve the uptake of PNA while trimethoprim's interaction with PNA my reveal a new inhibitory mechanism.

Keywords: Antibiotics; Antisense technologies; Peptide nucleic acids; Synergy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Dose-Response Relationship, Drug
Escherichia coli / drug effects*
Escherichia coli / genetics
Microbial Sensitivity Tests
Molecular Structure
Peptide Nucleic Acids / chemical synthesis
Peptide Nucleic Acids / chemistry
Peptide Nucleic Acids / pharmacology*
RNA, Messenger / drug effects*
RNA, Messenger / genetics
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Peptide Nucleic Acids
RNA, Messenger