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.
Ciara M McDonnell  1 ,  Magda Ghanim  2 ,  J Mike Southern  3 ,  Vincent P Kelly  4 ,  Stephen J Connon  5
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.
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