Multiple pathways of cross-resistance to glycopeptides and daptomycin in persistent MRSA bacteraemia

Chih Jung Chen*, Yhu Chering Huang, Cheng Hsu Chiu

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

28 Scopus citations

Abstract

Background: The development of non-susceptibility to glycopeptides and daptomycin in MRSA during persistent bacteraemia has become a significant therapeutic challenge. However, the in vivo evolution and mechanism of the dual resistance have remained incompletely understood. Methods: A series of MRSA blood isolates with incremental non-susceptibility to glycopeptides and daptomycin were consecutively recovered from a bacteraemic patient who was failing chemotherapy. The evolutionary pathways during conversion from a glycopeptide- and daptomycin-susceptible phenotype into a vancomycin-intermediate Staphylococcus aureus (VISA) and a daptomycin-resistant S. aureus (DRSA) phenotype were then traced by WGS of the isogenic strains. Results: A total of six non-synonymous mutations and three evolutionary pathways were identified during the development of the VISA/DRSA phenotype. The first pathway involved two steps of evolution, with an initial 1 bp insertion into yycH and a subsequent gain-in-function point mutation in mprF (S295L). The two mutations were correlated with heteroresistance to daptomycin/vancomycin and full development of the VISA/DRSA phenotype. The second pathway involved an 11 bp deletion mutation in yycH and point mutations at two genes, correlating with the development of the VISA phenotype and heteroresistance to daptomycin. Mutation in mprF (S295L) and a 5 bp deletion mutation in yycHwere identified in the third pathway and corresponded to conversion into the full VISA/DRSA phenotype. The mutations in yycH resulted in premature terminations of YycH with variable lengths. Conclusions: Multiple evolutionary pathways involving yycH and mprF can proceed simultaneously and may mediate cross-resistance to glycopeptides and daptomycin during persistent MRSA bacteraemia under antibiotic selective pressure.

Original languageEnglish
Pages (from-to)2965-2972
Number of pages8
JournalJournal of Antimicrobial Chemotherapy
Volume70
Issue number11
DOIs
StatePublished - 11 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

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