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Open Access Research article

Variable recombination dynamics during the emergence, transmission and ‘disarming’ of a multidrug-resistant pneumococcal clone

Nicholas J Croucher123, William P Hanage1, Simon R Harris2, Lesley McGee4, Mark van der Linden5, Herminia de Lencastre67, Raquel Sá-Leão6, Jae-Hoon Song8, Kwan Soo Ko9, Bernard Beall4, Keith P Klugman1011, Julian Parkhill2, Alexander Tomasz7, Karl G Kristinsson12 and Stephen D Bentley132*

Author Affiliations

1 Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston MA 02115, USA

2 Pathogen Genomics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK

3 Department of Infectious Disease Epidemiology, Imperial College, Norfolk Place, London W2 1NY, UK

4 Respiratory Diseases Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA

5 Institute for Medical Microbiology, National Reference Center for Streptococci, University Hospital, RWTH Aachen, Pauwelsstrasse 30, Aachen, Germany

6 Laboratory of Molecular Genetics, Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal

7 Laboratory of Microbiology, The Rockefeller University, New York, New York, USA

8 Samsung Medical Centre, Sungkyunkwan University School of Medicine and Asia Pacific Foundation for Infectious Disease, Seoul, South Korea

9 Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, South Korea

10 Hubert Department of Global Health, Rollins School of Public Health and Division of Infectious Diseases, School of Medicine, Emory University, Atlanta, Georgia, USA

11 Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases, Gauteng, South Africa

12 Clinical Microbiology Department, Landspitali University Hospital and University of Iceland, Reykjavík, Iceland

13 Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 0SP, UK

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BMC Biology 2014, 12:49  doi:10.1186/1741-7007-12-49

Published: 23 June 2014

Abstract

Background

Pneumococcal β-lactam resistance was first detected in Iceland in the late 1980s, and subsequently peaked at almost 25% of clinical isolates in the mid-1990s largely due to the spread of the internationally-disseminated multidrug-resistant PMEN2 (or Spain6B-2) clone of Streptococcus pneumoniae.

Results

Whole genome sequencing of an international collection of 189 isolates estimated that PMEN2 emerged around the late 1960s, developing resistance through multiple homologous recombinations and the acquisition of a Tn5253-type integrative and conjugative element (ICE). Two distinct clades entered Iceland in the 1980s, one of which had acquired a macrolide resistance cassette and was estimated to have risen sharply in its prevalence by coalescent analysis. Transmission within the island appeared to mainly emanate from Reykjavík and the Southern Peninsular, with evolution of the bacteria effectively clonal, mainly due to a prophage disrupting a gene necessary for genetic transformation in many isolates. A subsequent decline in PMEN2’s prevalence in Iceland coincided with a nationwide campaign that reduced dispensing of antibiotics to children in an attempt to limit its spread. Specific mutations causing inactivation or loss of ICE-borne resistance genes were identified from the genome sequences of isolates that reverted to drug susceptible phenotypes around this time. Phylogenetic analysis revealed some of these occurred on multiple occasions in parallel, suggesting they may have been at least temporarily advantageous. However, alteration of ‘core’ sequences associated with resistance was precluded by the absence of any substantial homologous recombination events.

Conclusions

PMEN2’s clonal evolution was successful over the short-term in a limited geographical region, but its inability to alter major antigens or ‘core’ gene sequences associated with resistance may have prevented persistence over longer timespans.

Keywords:
Bacterial evolution; Antibiotic resistance; Recombination; Mobile genetic elements; Coalescent analysis; Phylogeography