De-novo designed β-lysine derivatives can both augment and diminish the proliferation rates of E. coli through the action of Elongation Factor P

Ciara M McDonnell; Magda Ghanim; J Mike Southern; Vincent P Kelly; Stephen J Connon

doi:10.1016/j.bmcl.2022.128545

De-novo designed β-lysine derivatives can both augment and diminish the proliferation rates of E. coli through the action of Elongation Factor P

Bioorg Med Chem Lett. 2022 Mar 1:59:128545. doi: 10.1016/j.bmcl.2022.128545. Epub 2022 Jan 12.

Authors

Ciara M McDonnell¹, Magda Ghanim², J Mike Southern³, Vincent P Kelly⁴, Stephen J Connon⁵

Affiliations

¹ School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College Dublin 152-160 Pearse Street, Dublin 2, Ireland.
² School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin 152-160 Pearse Street, Dublin 2, Ireland.
³ School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College Dublin 152-160 Pearse Street, Dublin 2, Ireland. Electronic address: [email protected].
⁴ School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin 152-160 Pearse Street, Dublin 2, Ireland. Electronic address: [email protected].
⁵ School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College Dublin 152-160 Pearse Street, Dublin 2, Ireland. Electronic address: [email protected].

PMID: 35032607
DOI: 10.1016/j.bmcl.2022.128545

Abstract

An investigation into the effect of modified β-lysines on the growth rates of eubacterial cells is reported. It is shown that the effects observed are due to the post translational modification of Elongation Factor P (EFP) with these compounds catalysed by PoxA. PoxA was found to be remarkably promiscuous, which allowed the activity of a wide range of exogenous β-lysines to be examined. Two chain-elongated β-lysine derivatives which differ in aminoalkyl chain length by only 2 carbon units exhibited opposing biological activities - one promoting growth and the other retarding it. Both compounds were shown to operate through modification of EFP.

Keywords: Antibacterial agents; Elongation factor P; Peptide synthesis; Ribosome stalling; β-Lysine.

Publication types

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

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Cell Proliferation / drug effects
Deoxyribonucleases / metabolism*
Dose-Response Relationship, Drug
Drug Design*
Escherichia coli / cytology
Escherichia coli / drug effects*
Escherichia coli / metabolism
Escherichia coli Proteins / metabolism*
Lysine / analogs & derivatives*
Lysine / chemical synthesis
Lysine / chemistry
Lysine / pharmacology
Microbial Sensitivity Tests
Molecular Structure
Protein Processing, Post-Translational
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Escherichia coli Proteins
beta-lysine
Deoxyribonucleases
yjeA protein, E coli
Lysine