Loading...
Structures of lipoprotein signal peptidase II from Staphylococcus aureus complexed with antibiotics globomycin and myxovirescin.
Olatunji, Samir Yu, Xiaoxiao Bailey, Jonathan Huang, Chia-Ying Zapotoczna, Marta Bowen, Katherine Remškar, Maja Müller, Rolf Scanlan, Eoin M Geoghegan, Joan A
Olatunji, Samir
Yu, Xiaoxiao
Bailey, Jonathan
Huang, Chia-Ying
Zapotoczna, Marta
Bowen, Katherine
Remškar, Maja
Müller, Rolf
Scanlan, Eoin M
Geoghegan, Joan A
Citations
Altmetric:
Advisors
Editors
Other Contributors
Issue Date
2020-01-09
Submitted date
Files
Loading...
Open Access publication
Adobe PDF, 2.47 MB
Other Titles
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.
Citation
Nat Commun. 2020 Jan 9;11(1):140. doi: 10.1038/s41467-019-13724-y.
Publisher
Journal
PubMed ID
PubMed Central ID
Additional Links
Embedded video
Type
Article
Language
en
Description
Series/Report no.
ISSN
2041-1723