Genomic resistance in historical clinical isolates increased in frequency and mobility after the age of antibiotics

Abstract

Antibiotic resistance is frequently observed shortly after the clinical introduction of an antibiotic. Whether and how frequently that resistance occurred before the introduction is harder to determine, as isolates could not have been tested for resistance before an antibiotic was discovered. Historical collections, like the British National Collection of Type Cultures (NCTC), stretching back to 1885, provide a window into this history. Here we match 1,817 sequenced high-quality genomes from the NCTC collection to their respective year of isolation to study resistance genes before and concurrent with the age of antibiotics. Concordant with previous work, we find resistance genes in both pathogens and environmental samples before the age of antibiotics. While generally rare before the introduction of an antibiotic, we find an associated increase in frequency with antibiotic introduction. Finally, we observe a trend of resistance elements becoming both increasingly mobile and nested within multiple mobile elements as time goes on. More broadly, our findings suggest that likely-functional antibiotic resistance genes were circulating in clinically relevant isolates before the age of antibiotics, but human usage is associated with increasing both their overall prevalence and mobility. DATA SUMMARYGenome assemblies downloaded and analyzed are in Supplementary Table 1, and computational tools used are found in the Methods. The authors confirm all supporting data, code and protocols have been provided within the article or through supplementary data files. Impact statementHistorical collections of microbial isolates enable researchers to both investigate the past and identify interesting trends over time. In this study, we queried over 1,800 isolate genomes in one such collection for genomic variation linked to antibiotic resistance. We show that numerous isolates cultured before the introduction of a given antibiotic contain genomic variation linked to antibiotic resistance; however, this phenomenon remained relatively rare. We demonstrate a strong association between the year a given antibiotic was clinically introduced and a rise in prevalence of genomic resistance to that antibiotic. Finally, we show that while mobile elements are common throughout the isolates and timeframe analyzed, genomic resistance has become increasingly mobile as time has gone on. This study shows that as expected, the clinical introduction of a given antibiotic is correlated with an increase in resistance to that antibiotic but also was linked with increased mobility of genes and alleles conferring resistance. However, we note that the effect of deposition bias in the collection cannot be excluded. Our work also indicates that numerous microbial pangenomes of pathogens naturally contained genomic resistance to a given antibiotic even before anthropogenic use of that antibiotic. Taken together, we demonstrate that although human use may affect the prevalence and mobility of genomic resistance in clinical isolates; for most antibiotics, genomic resistance existed within the pangenomes of sampled pathogens prior to clinical introduction. Quantifying and understanding the impact of antibiotic introduction in the past helps us understand how the introduction of novel antibiotics can impact bacteria; allowing better reaction to novel resistant infections as they arise.