title: Deciphering the distance to antibiotic resistance for the pneumococcus using genome sequencing data.
abstract: Advances in genome sequencing technologies and genome-wide association studies (GWAS) have provided unprecedented insights into the molecular basis of microbial phenotypes and enabled the identification of the underlying genetic variants in real populations. However, utilization of genome sequencing in clinical phenotyping of bacteria is challenging due to the lack of reliable and accurate approaches. Here, we report a method for predicting microbial resistance patterns using genome sequencing data. We analyzed whole genome sequences of 1,680 Streptococcus pneumoniae isolates from four independent populations using GWAS and identified probable hotspots of genetic variation which correlate with phenotypes of resistance to essential classes of antibiotics. With the premise that accumulation of putative resistance-conferring SNPs, potentially in combination with specific resistance genes, precedes full resistance, we retrogressively surveyed the hotspot loci and quantified the number of SNPs and/or genes, which if accumulated would confer full resistance to an otherwise susceptible strain. We name this approach the 'distance to resistance'. It can be used to identify the creep towards complete antibiotics resistance in bacteria using genome sequencing. This approach serves as a basis for the development of future sequencing-based methods for predicting resistance profiles of bacterial strains in hospital microbiology and public health settings.
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen 6525 GA, The Netherlands.|Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen 6525 GA, The Netherlands.|Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands.
authors.forename: Fredrick M
authors.initials: FM
authors.lastname: Mobegi
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen 6525 GA, The Netherlands.
authors.forename: Amelieke J H
authors.initials: AJ
authors.lastname: Cremers
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen 6525 GA, The Netherlands.
authors.forename: Marien I
authors.initials: MI
authors.lastname: de Jonge
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 15A, UK.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Bentley
authors.affiliation: Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen 6525 GA, The Netherlands.
authors.forename: Sacha A F T
authors.initials: SA
authors.lastname: van Hijum
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen 6525 GA, The Netherlands.|Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen 6525 GA, The Netherlands.|Faculty of Veterinary Medicine, Department of Infectious Diseases and Immunology, Utrecht University, Utrecht 3508 TD, The Netherlands.
authors.forename: Aldert
authors.initials: A
authors.lastname: Zomer
mesh_terms: D004352:Drug Resistance, Microbial; D019143:Evolution, Molecular; D016680:Genome, Bacterial; D055106:Genome-Wide Association Study; D008826:Microbial Sensitivity Tests; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA / Q000379:methods*; D013296:Streptococcus pneumoniae / Q000145:classification* / Q000187:drug effects / Q000235:genetics*