Remodeling of pSK1 Family Plasmids and Enhanced Chlorhexidine Tolerance in a Dominant Hospital Lineage of Methicillin-Resistant Staphylococcus aureus.

Sarah L Baines,Deborah A Williamson,Benjamin P Howden,Neville Firth,Glen P Carter,Torsten Seemann,Timothy P Stinear,Anders Gonçalves Da Silva,Slade O Jensen

doi:10.1128/aac.02356-18

Abstract

Staphylococcus aureus is a significant human pathogen whose evolution and adaptation have been shaped in part by mobile genetic elements (MGEs), facilitating the global spread of extensive antimicrobial resistance. However, our understanding of the evolutionary dynamics surrounding MGEs, in particular, how changes in the structure of multidrug resistance (MDR) plasmids may influence important staphylococcal phenotypes, is incomplete. Here, we undertook a population and functional genomics study of 212 methicillin-resistant S. aureus (MRSA) sequence type 239 (ST239) isolates collected over 32 years to explore the evolution of the pSK1 family of MDR plasmids, illustrating how these plasmids have coevolved with and contributed to the successful adaptation of this persistent MRSA lineage. Using complete genomes and temporal phylogenomics, we reconstructed the evolution of the pSK1 family lineage from its emergence in the late 1970s and found that multiple structural variants have arisen. Plasmid maintenance and stability were linked to IS256- and IS257-mediated chromosomal integration and disruption of the plasmid replication machinery. Overlaying genomic comparisons with phenotypic susceptibility data for gentamicin, trimethoprim, and chlorhexidine, it appeared that pSK1 has contributed to enhanced resistance in ST239 MRSA isolates through two mechanisms: (i) acquisition of plasmid-borne resistance mechanisms increasing the rates of gentamicin resistance and reduced chlorhexidine susceptibility and (ii) changes in the plasmid configuration linked with further enhancement of chlorhexidine tolerance. While the exact mechanism of enhanced tolerance remains elusive, this research has uncovered a potential evolutionary response of ST239 MRSA to biocides, one of which may contribute to the ongoing persistence and adaptation of this lineage within health care institutions.

Highlights

Staphylococcus aureus is a significant human pathogen whose evolution and adaptation have been shaped in part by mobile genetic elements (MGEs), facilitating the global spread of extensive antimicrobial resistance
An in silico examination of the temporally diverse, global collection of 531 sequence type 239 (ST239) isolates looking for orthologs of the pSK1 genes revealed that pSK1-like plasmids have been maintained in the ST239 population over time but are largely harbored by a single clade, the Australian clade (Fig. 1A)
This suggested the extended coevolution of the pSK1 plasmid family and the Australian ST239 clade and subsequently indicated that this population could serve as a model in which to study the evolution of multidrug resistance (MDR) staphylococcal plasmids and the impact that extended plasmid maintenance may have on antimicrobial resistance and biocide tolerance

Summary

Introduction

Staphylococcus aureus is a significant human pathogen whose evolution and adaptation have been shaped in part by mobile genetic elements (MGEs), facilitating the global spread of extensive antimicrobial resistance. Mobile genetic elements (MGEs) play a central role in microbial evolution, serving as a mechanism by which genetic material can be transferred, disseminated, and rearranged, allowing for rapid adaptation to new and changing environments Nowhere is this more apparent than in the global dissemination of genes encoding. We have previously described the long-term evolution of ST239 MRSA in eastern Australian hospitals to be one of convergent and adaptive evolution of two genetically distinct ST239 clades (termed the Australian and Asian-Australian clades) toward increased antimicrobial resistance at the cost of attenuated virulence [15] This initial work largely focused on changes occurring within conserved regions of the genome, with exploration of the accessory genome being limited. An outbreak of ST239 MRSA in the United Kingdom in the early 2000s was attributed to the presence of a plasmid-borne qacA gene and predicted biocide tolerance [29, 30]

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