Sequential acquisition of virulence and fluoroquinolone resistance has shaped the evolution ofEscherichia coliST131

Abstract

Escherichia coli ST131 is the most frequently isolated fluoroquinolone-resistant (FQR) E. coli clone worldwide and a major cause of urinary tract and bloodstream infections. Although originally identified through its association with the CTX-M-15 extended-spectrum ␤-lactamase resistance gene, global genomic epidemiology studies have failed to resolve the geographical and temporal origin of the ST131 ancestor. Here, we developed a framework for the reanalysis of publically available genomes from different countries and used this data set to reconstruct the evolutionary steps that led to the emergence of FQR ST131. Using Bayesian estimation, we show that point mutations in chromosomal genes that confer FQR coincide with the first clinical use of fluoroquinolone in 1986 and illustrate the impact of this pivotal event on the rapid population expansion of ST131 worldwide from an apparent origin in North America. Furthermore, we identify virulence factor acquisition events that predate the development of FQR, suggesting that the gain of virulence-associated genes followed by the tandem development of antibiotic resistance primed the successful global dissemination of ST131.IMPORTANCE Escherichia coli sequence type 131 (ST131) is a recently emerged and globally disseminated multidrug-resistant clone frequently associated with human urinary tract and bloodstream infections. In this study, we have used two large publically available genomic data sets to define a number of critical steps in the evolution of this important pathogen. We show that resistance to fluoroquinolones, a class of broad-spectrum antibiotic used extensively in human medicine and veterinary practice, developed in ST131 soon after the introduction of these antibiotics in the United States, most likely in North America. We also mapped the acquisition of several fitness and virulence determinants by ST131 and demonstrate these events occurred prior to the development of fluoroquinolone resistance. Thus, ST131 has emerged by stealth, first acquiring genes associated with an increased capacity to cause human infection, and then gaining a resistance armory that has driven its massive population expansion across the globe.

Systematic longitudinal survey of invasive Escherichia coli in England demonstrates a stable population structure only transiently disturbed by the emergence of ST131

“…This is supported by evidence that both drug-resistant (ST131) and drug-susceptible (ST73) lineages are equally successful in being maintained in this reservoir and that drug resistance as a whole in the population is not increasing, demonstrating that antibiotic resistance is not a primary driver of success or prevalence in this niche. In the case of ST131, this is supported by the findings of Ben Zakour et al (2016), who reported that virulence determinants were acquired before the emergence of the fluoroquinolone-resistant C clade (Ben Zakour et al 2016). According to this hypothesis, the primary forces shaping the population are not those within the hospital environment but are due to competition within the gut commensal niche in the broader human population, where antibiotic use is more sporadic than in the hospital population.…”

“…3). The assignment of isolates to clades was confirmed by investigating six previously reported clade specific SNPs for B, C, C1, and C2 (Ben Zakour et al 2016). This confirmed our assignment of isolates to clades and revealed that the three fimH27 isolates in the B clade most likely belong to the B0 clade defined by Ben Zakour et al (2016).…”

“…ST131 has received particular attention, following its apparent emergence in the 2000s, due to its rapid global dissemination and frequent multidrug-resistant (MDR) phenotype (Nicolas-Chanoine et al 2014). This has led to ST131 being well characterized by publications that propose biological explanations for its emergence and spread (Price et al 2013;Petty et al 2014;Salipante et al 2015;Ben Zakour et al 2016;Stoesser et al 2016). Other common STs are less well characterized despite their association with disease, in part because they are less often defined as MDR and because ST131 is an important player in the broader global problem of increasing antibiotic resistance in Gram-negative bacteria, with clinical isolates that are resistant to aminoglycosides, fluoroquinolones, extended-spectrum beta-lactamases, carbapenems, and colistin beginning to emerge (Chen et al 2014;Zhang et al 2014;Liu et al 2016;Skov and Monnet 2016).…”

Correlated Mutations and Homologous Recombination Within Bacterial Populations

“…We obtained a curated list of 185 E. coli sequence type 131 (ST131) isolates from two recent studies (Price et al 2013;Petty et al 2014;Ben Zakour et al 2016), and a total list of 1216 S. pneumoniae isolates, which consisted of all isolates from the seven largest clusters in a longitudinal pneumococcal carriage study (Chewapreecha et al 2014). For each species, we applied a reference-based approach to generate whole-genome alignments from Illumina read data.…”

“…We used whole genome sequences from a recently emerged multidrug-resistant Escherichia coli clone, sequence type 131 (ST131) containing 185 isolates (Price et al 2013;Petty et al 2014;Ben Zakour et al 2016), and 1216 Streptococcus pneumoniae isolates in a longitudinal pneumococcal carriage study (Chewapreecha et al 2014), two species that are well known for horizontal transfer and recombination (Lorenz and Wackernagel 1994). For each dataset, and several subtypes or clades, we calculated sample diversity and correlation functions, and inferred the bulk population parameters (Table 2) by fittingP ð2Þ s;2 ðlÞ (see Appendix G for details of sequence analysis).…”