Escherichia coli associated with urinary tract infections and bacteremia has been intensively investigated, including recent work focusing on the virulent, globally disseminated, multidrug-resistant lineage ST131. To contextualize ST131 within the broader E. coli population associated with disease, we used genomics to analyze a systematic 11-yr hospital-based survey of E. coli associated with bacteremia using isolates collected from across England by the British Society for Antimicrobial Chemotherapy and from the Cambridge University Hospitals NHS Foundation Trust. Population dynamics analysis of the most successful lineages identified the emergence of ST131 and ST69 and their establishment as two of the five most common lineages along with ST73, ST95, and ST12. The most frequently identified lineage was ST73. Compared to ST131, ST73 was susceptible to most antibiotics, indicating that multidrug resistance was not the dominant reason for prevalence of E. coli lineages in this population. Temporal phylogenetic analysis of the emergence of ST69 and ST131 identified differences in the dynamics of emergence and showed that expansion of ST131 in this population was not driven by sequential emergence of increasingly resistant subclades. We showed that over time, the E. coli population was only transiently disturbed by the introduction of new lineages before a new equilibrium was rapidly achieved. Together, these findings suggest that the frequency of E. coli lineages in invasive disease is driven by negative frequency-dependent selection occurring outside of the hospital, most probably in the commensal niche, and that drug resistance is not a primary determinant of success in this niche.

Escherichia coli is a major cause of bloodstream and urinary tract infections globally. The wide dissemination of multidrug-resistant (MDR) strains of extraintestinal pathogenic E. coli (ExPEC) poses a rapidly increasing public health burden due to narrowed treatment options and increased risk of failure to clear an infection. Here, we present a detailed population genomic analysis of the ExPEC ST131 clone, in which we seek explanations for its success as an emerging pathogenic strain beyond the acquisition of antimicrobial resistance (AMR) genes. We show evidence for evolution toward separate ecological niches for the main clades of ST131 and differential evolution of anaerobic metabolism, key colonization, and virulence factors. We further demonstrate that negative frequency-dependent selection acting across accessory loci is a major mechanism that has shaped the population evolution of this pathogen. IMPORTANCE Infections with multidrug-resistant (MDR) strains of Escherichia coli are a significant global public health concern. To combat these pathogens, we need a deeper understanding of how they evolved from their background populations. By understanding the processes that underpin their emergence, we can design new strategies to limit evolution of new clones and combat existing clones. By combining population genomics with modelling approaches, we show that dominant MDR clones of E. coli are under the influence of negative frequency-dependent selection, preventing them from rising to fixation in a population. Furthermore, we show that this selection acts on genes involved in anaerobic metabolism, suggesting that this key trait, and the ability to colonize human intestinal tracts, is a key step in the evolution of MDR clones of E. coli.

Objectives: Efforts to treat Escherichia coli infections are increasingly being compromised by the rapid, global spread of antimicrobial resistance (AMR). Whilst AMR in E. coli has been extensively investigated in resource-rich settings, in sub-Saharan Africa molecular patterns of AMR are not well described. In this study, we have begun to explore the population structure and molecular determinants of AMR amongst E. coli isolates from Malawi. Methods: Ninety-four E. coli isolates from patients admitted to Queen’s Hospital, Malawi, were whole-genome sequenced. The isolates were selected on the basis of diversity of phenotypic resistance profiles and clinical source of isolation (blood, CSF and rectal swab). Sequence data were analysed using comparative genomics and phylogenetics. Results: Our results revealed the presence of five clades, which were strongly associated with E. coli phylogroups A, B1, B2, D and F. We identified 43 multilocus STs, of which ST131 (14.9%) and ST12 (9.6%) were the most common. We identified 25 AMR genes. The most common ESBL gene was blaCTX-M-15 and it was present in all five phylogroups and 11 STs, and most commonly detected in ST391 (4/4 isolates), ST648 (3/3 isolates) and ST131 [3/14 (21.4%) isolates]. Conclusions: This study has revealed a high diversity of lineages associated with AMR, including ESBL and fluoroquinolone resistance, in Malawi. The data highlight the value of longitudinal bacteraemia surveillance coupled with detailed molecular epidemiology in all settings, including low-income settings, in describing the global epidemiology of ESBL resistance.