Diversification of Colonization Factors in a Multidrug-Resistant Escherichia coli Lineage Evolving under Negative Frequency-Dependent Selection

Abstract

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.

Genomic and Functional Analysis of Emerging Virulent and Multidrug-Resistant Escherichia coli Lineage Sequence Type 648

“…So far, this has resulted in a relatively steady population structure of different phylogenetic lineages only disrupted by the emergence of ST131, as demonstrated in a large-scale bacteremia study performed in the United Kingdom. To also predict the invasive success of ST648, we applied the NFDS model to the above-mentioned UK BSAC bacteremia sample set (26). Our results show that ST648 will expectedly increase to a stable frequency, with a maximum near 1.5% among all populations (Fig.…”

Producing Polished Prokaryotic Pangenomes with the Panaroo Pipeline

“…This can have profound implications for the resulting estimates of the pangenome whereby a higher number genomes leads to a higher number of errors (16,17). Such errors can cause difficulties in any downstream mod-D R A F T eling of the pangenome, such as the modeling of negative frequency-dependent selection (NFDS) acting through the loci in the accessory genome (18,19). Errors can be introduced into pangenome analyses by fragmented assemblies, mis-annotation, contamination and mis-assembly.…”

Non-clonal emergence of colistin resistance associated with mutations in the BasRS two-component system in Escherichia coli bloodstream isolates

“…Based on a core genome alignment of 874 kbp, we did not observe direct transmission of colistin-resistant strains between patients (Figure 1A). Three colistin-resistant strains (strains I1121, H2129, and G821) belonged to the globally disseminated ST131 clone, and all three were dispersed throughout the multidrug-resistant clade C of ST131(Figure 1A, 1B) (3, 50). This indicates that the ST131 strains in this study have independently acquired colistin resistance.…”

“…Escherichia coli is a Gram-negative opportunistic pathogen that is a common cause of bloodstream, urinary tract, and enteric infections (1). The rising prevalence of antibiotic resistance in E. coli , in part due to the increasing global spread of the successful multidrug-resistant clade C lineage of ST131, may limit options for future treatments of infections (2, 3). Due to the emergence and spread of multidrug-resistant clones of E. coli and other Enterobacteriaceae, and the lack of new antibiotics targeting Gram-negative bacteria, colistin (polymyxin E) is increasingly used, despite its neuro- and nephrotoxic side effects, in the treatment of clinical infections with multidrug-resistant and carbapenem-resistant E. coli and other Enterobacteriaceae (4–6).…”