A Polymorphism in leuS Confers Reduced Susceptibility to GSK2251052 in a Clinical Isolate of Staphylococcus aureus

Arya Gupta; Carmine Monteferrante; Dace Rasina; Gundars Leitis; Christopher P Randall; Jennifer H Tomlinson; Aigars Jirgensons; Wil H F Goessens; John P Hays; Alex J O'Neill

doi:10.1128/AAC.02940-15

A Polymorphism in leuS Confers Reduced Susceptibility to GSK2251052 in a Clinical Isolate of Staphylococcus aureus

Antimicrob Agents Chemother. 2016 Apr 22;60(5):3219-21. doi: 10.1128/AAC.02940-15. Print 2016 May.

Affiliations

¹ School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom.
² Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
³ Latvian Institute of Organic Synthesis, Riga, Latvia.
⁴ School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom a.j.oneill@leeds.ac.uk.

Abstract

GSK2251052 is a broad-spectrum antibacterial inhibitor of leucyl tRNA-synthetase (LeuRS) that has been evaluated in phase II clinical trials. Here, we report the identification of a clinical isolate of Staphylococcus aureus that exhibits reduced susceptibility to GSK2251052 without prior exposure to the compound and demonstrate that this phenotype is attributable to a single amino acid polymorphism (P329) within the editing domain of LeuRS.

Publication types

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

MeSH terms

Anti-Bacterial Agents / pharmacology*
Bacterial Proteins / genetics
Boron Compounds / pharmacology*
Leucine-tRNA Ligase / genetics
Leucine-tRNA Ligase / metabolism
Polymorphism, Genetic / genetics*
Staphylococcus aureus / drug effects*
Staphylococcus aureus / genetics
Staphylococcus aureus / metabolism

Substances

3-(aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole
Anti-Bacterial Agents
Bacterial Proteins
Boron Compounds
Leucine-tRNA Ligase