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.
Highlights
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
We report the use of genome sequencing and GWAS to investigate single nucleotide polymorphisms (SNPs) and genes associated with resistance to four essential classes of antibiotics; collectively referred to as antibiotic resistance hereafter
We identified SNPs associated with resistance to trimethoprim and cotrimoxazole in various genes encoding enzymes involved in folate metabolism, including dyr, folE, and folP (Fig. 2; Supplementary Tables S3–S4), and SNPs in genes implicated in resistance to other essential antibiotics like penicillin
Summary
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. Significant advances in high-throughput genome sequencing technologies and bacterial genome-wide association studies (GWAS) allow identification of statistical association between plausible causal genetic variants and microbial phenotypes in real populations[7]. This approach was recently used to identify the single nucleotide polymorphisms (SNPs) in DNA that may confer beta-lactam resistance in S. pneumoniae[6]. This study serves as a foundation for the development of future technologies that could utilize genomic sequencing to analyze the molecular epidemiological trends for bacterial strains reliably, and provide an early-warning measure for the edge towards antimicrobial resistance, crucially informing on clinical intervention strategies
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