Siderophore biosynthesis coordinately modulated the virulence-associated interactive metabolome of uropathogenic Escherichia coli and human urine

Abstract

Uropathogenic Escherichia coli (UPEC) growth in women’s bladders during urinary tract infection (UTI) incurs substantial chemical exchange, termed the “interactive metabolome”, which primarily accounts for the metabolic costs (utilized metabolome) and metabolic donations (excreted metabolome) between UPEC and human urine. Here, we attempted to identify the individualized interactive metabolome between UPEC and human urine. We were able to distinguish UPEC from non-UPEC by employing a combination of metabolomics and genetics. Our results revealed that the interactive metabolome between UPEC and human urine was markedly different from that between non-UPEC and human urine, and that UPEC triggered much stronger perturbations in the interactive metabolome in human urine. Furthermore, siderophore biosynthesis coordinately modulated the individualized interactive metabolome, which we found to be a critical component of UPEC virulence. The individualized virulence-associated interactive metabolome contained 31 different metabolites and 17 central metabolic pathways that were annotated to host these different metabolites, including energetic metabolism, amino acid metabolism, and gut microbe metabolism. Changes in the activities of these pathways mechanistically pinpointed the virulent capability of siderophore biosynthesis. Together, our findings provide novel insights into UPEC virulence, and we propose that siderophores are potential targets for further discovery of drugs to treat UPEC-induced UTI.

Challenges and emergent solutions for LC‐MS/MS based untargeted metabolomics in diseases

“…These strains were found to influence the metabolome, which differentiated pathogenic and non‐pathogenic strains . It was found that the metabolomes of the pathogenic strains with genetic deletions of the enzymes that regulate these metabolites were similar to non‐pathogenic strains, thus revealing these metabolites as key determinants of urinary tract infections …”

“…15 It was found that the metabolomes of the pathogenic strains with genetic deletions of the enzymes that regulate these metabolites were similar to non-pathogenic strains, thus revealing these metabolites as key determinants of urinary tract infections. 151 MicroRNAs (miRNAs) regulate the metabolic reprogram in cancer and metabolic disorders. [152][153][154] Because individual miRNA potentially regulate hundreds of proteins and metabolites, a large-scale coupling of miRNA profiles with metabolomics allows the miRNA-metabolite relationships to be mapped in a high-throughput manner.…”

Metabolic Adaptations of Uropathogenic E. coli in the Urinary Tract

“…However, the disease is predominantly caused by Uropathogenic E. coli (UPEC; Schulz, 2011; Flores-Mireles et al, 2015; Su et al, 2016b), which accounts for up to 75% of all cases (Foxman, 2002, 2003; Martinez and Hultgren, 2002) and 95% of community-acquired cases (Kucheria et al, 2005). …”

Mass spectrometry and associated technologies delineate the advantageously biomedical capacity of siderophores in different pathogenic contexts

“…A recent study showed that Ent-Cipro, a synthetic siderophore-antibiotic conjugate based on the native Ent (enterobactin, a kind of siderophore) platform affords targeted antibacterial activity against Escherichia coli strains that express the pathogen-associated IroA gene cluster (Neumann et al, 2018). Furthermore, yersiniabactin and salmochelin produced by E. coli strains have been proven to cause infection in UTIs by previous experiments, and lead to new antibiotics against these two siderophores as a potential strategy to prevent and treat UTIs (Henderson et al, 2009;Su et al, 2016;Ohlemacher et al, 2017). Furthermore, Rakin et al (2012) demonstrated that there are several siderophore iron-scavenging systems apart from Ybt in another highly virulent genus-Yersinia.…”

“…Specifically, different types of mass spectrometry, such as inductively coupled plasma-mass spectrometry (ICP-MS), matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), electrospray-ionization mass spectrometry (ESI-MS), affinity selection-mass spectrometry (ASMS), laser ablation electrospray ionization-mass spectrometry (LAESI-MS), and mass spectrometry imaging (MSI) techniques (MALDI-MS imaging and DESI-MS imaging), have been broadly used to identify siderophores (Pluhacek et al, 2016;Su et al, 2016;Hagan et al, 2017;Walker et al, 2017). In short, mass spectrometry and associated technologies are emerging as novel tools for the annotation of chemical, biological, and biomedical applications of pathogen-associated siderophores.…”