AbstractAntimicrobial resistance (AMR) is a major problem for human and animal health, and can co-vary with features of the bacterial genome, its ecological context, and with other traits. Here, we present an integrated study of AMR in the porcine zoonotic pathogen, Streptococcus suis. Collecting a diverse panel of 678 isolates, we obtained replicated measures of Minimum Inhibitory Concentration (MIC) for 16 widely used antimicrobials, from eight distinct classes. Then using whole genome sequences for each isolate, we identified 42 candidate AMR alleles, of which 21 were novel for S. suis. The presence of these alleles explains most of the observed variation in MIC but there was also unexplained variation, partly due to alleles of small effect, and epistatic interactions. We find that MIC varies with S. suis genetic background and country, but less so with clinical phenotype, serotype or over time. These ecological patterns are largely explained by allele prevalence. MIC values for different antibiotic classes positively correlate with one another, but there is limited evidence of direct pleiotropy, where single alleles confer resistance to multiple drug classes. Instead, this covariation is due to alleles for separate classes appearing together, but not necessarily in the same genomic region. The result is a significant excess of multi-drug resistant isolates. Indeed, we found more isolates that carried resistance alleles to five classes of antibiotics than isolates than carried no resistance alleles. We discuss the implications of our results for combatting AMR in S. suis, and for understanding multi-drug resistance in bacteria.ImportanceStreptococcus suis is a bacterium that causes serious disease with significant welfare and economic impacts for the global pig industry, and meningitis in humans. Antibiotics are the principal treatment for these bacteria, and so the evolution of antibiotic resistance presents a major problem for global food security and human health. We tested susceptibility to 16 different antibiotics in a global sample of 678 S. suis isolates. Using comparative analysis of whole genome sequences, we identified existing and novel genetic variants that affect resistance. Results show that, in most cases, the presence/absence of these alleles is a good predictor of resistance levels, which could help facilitate resistance monitoring through genome sequencing. We also observe a tendency for AMR variants to co-occur together in some S. suis isolates. These multi-drug resistant isolates should be monitored as a priority.
Massive Diversity in Whole-Genome Sequences of Streptococcus suis Strains from Infected Pigs in Switzerland