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

Samir Olatunji, Xiaoxiao Yu, Jonathan Bailey, Chia-Ying Huang, Marta Zapotoczna, Katherine Bowen, Maja Remškar, Rolf Müller, Eoin M. Scanlan, Joan A. Geoghegan, Vincent Olieric and Martin Caffrey ()
Additional contact information
Samir Olatunji: Trinity College Dublin
Xiaoxiao Yu: Trinity College Dublin
Jonathan Bailey: Trinity College Dublin
Chia-Ying Huang: Paul Scherrer Institute
Marta Zapotoczna: Trinity College Dublin
Katherine Bowen: Trinity College Dublin
Maja Remškar: Saarland University Campus E8 1
Rolf Müller: Saarland University Campus E8 1
Eoin M. Scanlan: Trinity College Dublin
Joan A. Geoghegan: Trinity College Dublin
Vincent Olieric: Paul Scherrer Institute
Martin Caffrey: Trinity College Dublin

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: 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.

Date: 2020
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-019-13724-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-13724-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-13724-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().