Structures of lipoprotein signal peptidase II from Staphylococcus aureus complexed with antibiotics globomycin and myxovirescin

Research output: Contribution to journalArticlepeer-review

Authors

  • Samir Olatunji
  • Xiaoxiao Yu
  • Jonathan Bailey
  • Chia-Ying Huang
  • Marta Zapotoczna
  • Katherine Bowen
  • Maja Remškar
  • Rolf Müller
  • Eoin M Scanlan
  • Vincent Olieric
  • Martin Caffrey

Colleges, School and Institutes

External organisations

  • Trinity College Dublin
  • Paul Scherrer Institute
  • Saarland University Campus E8 1

Abstract

Antimicrobial resistance is a major global threat that calls for new antibiotics. Globomycin and myxovirescin are two natural antibiotics that target the lipoprotein-processing enzyme, LspA, thereby compromising the integrity of the bacterial cell envelope. As part of a project aimed at understanding their mechanism of action and for drug development, we provide high-resolution crystal structures of the enzyme from the human pathogen methicillin-resistant Staphylococcus aureus (MRSA) complexed with globomycin and with myxovirescin. Our results reveal an instance of convergent evolution. The two antibiotics possess different molecular structures. Yet, they appear to inhibit identically as non-cleavable tetrahedral intermediate analogs. Remarkably, the two antibiotics superpose along nineteen contiguous atoms that interact similarly with LspA. This 19-atom motif recapitulates a part of the substrate lipoprotein in its proposed binding mode. Incorporating this motif into a scaffold with suitable pharmacokinetic properties should enable the development of effective antibiotics with built-in resistance hardiness.

Details

Original languageEnglish
Article number140
Number of pages11
JournalNature Communications
Volume11
Issue number1
Publication statusPublished - 9 Jan 2020

Keywords

  • Aspartic Acid Endopeptidases/metabolism, Bacterial Proteins/metabolism, Binding Sites/physiology, Cell Membrane/drug effects, Crystallography, X-Ray, Drug Resistance, Bacterial/genetics, Macrolides/metabolism, Methicillin-Resistant Staphylococcus aureus/enzymology, Peptides/metabolism, Protein Binding/physiology, Protein Structure, Tertiary