Yersiniabactin is a quorum-sensing autoinducer and siderophore in uropathogenic Escherichia coli.

Siderophores are secreted ferric ion chelators used to obtain iron in nutrient-limited environmental niches, including human hosts. While all Escherichia coli express the enterobactin (Ent) siderophore system, isolates from patients with urinary tract infections additionally express the genetically distinct yersiniabactin (Ybt) siderophore system. To determine whether the Ent and Ybt systems are functionally redundant for iron uptake, we compared the growth of different isogenic siderophore biosynthetic mutants in the presence of transferrin, a human iron-binding protein. We observed that Ybt expression does not compensate for deficient Ent expression following low-density inoculation. Using transcriptional and product analysis, we found this non-redundancy to be attributable to a density-dependent transcriptional stimulation cycle in which Ybt functions as an autoinducer. These results distinguish the Ybt system as a combined quorum-sensing and siderophore system. These functions may reflect Ybt as a public good within bacterial communities or as an adaptation to confined, subcellular compartments in infected hosts. This combined functionality may contribute to the extraintestinal pathogenic potential of E. coli and related Enterobacterales.IMPORTANCEPatients with urinary tract infections are often infected with Escherichia coli strains carrying adaptations that increase their pathogenic potential. One of these adaptations is the accumulation of multiple siderophore systems, which scavenge iron for nutritional use. While iron uptake is important for bacterial growth, the increased metabolic costs of siderophore production could diminish bacterial fitness during infections. In a siderophore-dependent growth condition, we show that the virulence-associated yersiniabactin siderophore system in uropathogenic E. coli is not redundant with the ubiquitous E. coli enterobactin system. This arises not from differences in iron-scavenging activity but because yersiniabactin is preferentially expressed during bacterial crowding, leaving bacteria dependent upon enterobactin for growth at low cell density. Notably, this regulatory mode arises because yersiniabactin stimulates its own expression, acting as an autoinducer in a previously unappreciated quorum-sensing system. This unexpected result connects quorum-sensing with pathogenic potential in E. coli and related Enterobacterales.

Yersiniabactin is a quorum sensing autoinducer and siderophore in uropathogenic Escherichia coli.

Siderophores are secreted ferric ion chelators used to obtain iron in nutrient-limited environmental niches, including human hosts. While all E. coli encode the enterobactin (Ent) siderophore system, isolates from patients with urinary tract infections additionally encode the genetically distinct yersiniabactin (Ybt) siderophore system. To determine whether the Ent and Ybt systems are functionally redundant for iron uptake, we compared growth of different isogenic siderophore biosynthesis mutants in the presence of transferrin, a human iron-binding protein. We observed that the Ybt system does not compensate for loss of the Ent system during siderophore-dependent, low density growth. Using transcriptional and product analysis, we found that this non-redundancy is attributable to a density-dependent transcriptional stimulation cycle in which Ybt assume an additional autoinducer function. These results distinguish the Ybt system as a combined quorum-sensing and siderophore system. These functions may reflect Ybt as a public good within bacterial communities or as an adaptation to confined, subcellular compartments in infected hosts. The efficiency of this arrangement may contribute to the extraintestinal pathogenic potential of E. coli and related Enterobacterales. IMPORTANCE: Urinary tract infections (UTIs) are one of the most common human bacterial infections encountered by physicians. Adaptations that increase the pathogenic potential of commensal microbes such as E.coli are of great interest. One potential adaptation observed in clinical isolates is accumulation of multiple siderophore systems, which scavenge iron for nutritional use. While iron uptake is important for bacterial growth, the increased metabolic costs of siderophore production could diminish bacterial fitness during infections. In a siderophore-dependent growth conditions, we show that the virulence-associated yersiniabactin siderophore system in uropathogenic E. coli is not redundant with the ubiquitous E. coli enterobactin system. This arises not from differences in iron scavenging activity but because yersiniabactin is preferentially expressed during bacterial crowding, leaving bacteria dependent upon enterobactin for growth at low cell density. Notably, this regulatory mode arises because yersiniabactin stimulates its own expression, acting as an autoinducer in a previously unappreciated quorum-sensing system. This unexpected result connects quorum-sensing with pathogenic potential in E. coli and related Enterobacterales.

E. coli catheter-associated urinary tract infections are associated with distinctive virulence and biofilm gene determinants.

Urinary catheterization facilitates urinary tract colonization by E. coli and increases infection risk. Here, we aimed to identify strain-specific characteristics associated with the transition from colonization to infection in catheterized patients. In a single-site study population, we compared E. coli isolates from patients with catheter-associated asymptomatic bacteriuria (CAASB) to those with catheter-associated urinary tract infection (CAUTI). CAUTI isolates were dominated by a phylotype B2 subclade containing the multidrug-resistant ST131 lineage relative to CAASB isolates, which were phylogenetically more diverse. A distinctive combination of virulence-associated genes was present in the CAUTI-associated B2 subclade. Catheter-associated biofilm formation was widespread among isolates and did not distinguish CAUTI from CAASB strains. Preincubation with CAASB strains could inhibit catheter colonization by multiple ST131 CAUTI isolates. Comparative genomic analysis identified a group of variable genes associated with high catheter biofilm formation present in both CAUTI and CAASB strains. Among these, ferric citrate transport (Fec) system genes were experimentally associated with enhanced catheter biofilm formation using reporter and fecA deletion strains. These results are consistent with a variable role for catheter biofilm formation in promoting CAUTI by ST131-like strains or resisting CAUTI by lower-risk strains that engage in niche exclusion.

The Yersinia High-Pathogenicity Island Encodes a Siderophore-Dependent Copper Response System in Uropathogenic Escherichia coli.

Siderophores are iron chelators used by microbes to bind and acquire iron, which, once in the cell, inhibits siderophore production through feedback repression mediated by the ferric uptake repressor (Fur). Yersiniabactin (Ybt), a siderophore associated with enhanced pathogenic potential among Enterobacteriaceae, also binds copper ions during human and experimental murine infections. In contrast to iron, we found that extracellular copper ions rapidly and selectively stimulate Ybt production in extraintestinal pathogenic Escherichia coli. The stimulatory pathway requires formation of an extracellular copper-Ybt (Cu(II)-Ybt) complex, internalization of Cu(II)-Ybt entry through the canonical TonB-dependent outer membrane transporter, and Fur-independent transcriptional regulation by the specialized transcription factor YbtA. Dual regulation by iron and copper is consistent with a multifunctional metallophore role for Ybt. Feed-forward regulation is typical of stress responses, implicating Ybt in prevention of, or response to, copper stress during infection pathogenesis. IMPORTANCE Interactions between bacteria and transition metal ions play an important role in encounters between humans and bacteria. Siderophore systems have long been prominent mediators of these interactions. These systems secrete small-molecule chelators that bind oxidized iron(III) and express proteins that specifically recognize and import these complexes as a nutritional iron source. While E. coli and other Enterobacteriaceae secrete enterobactin, clinical isolates often secrete an additional siderophore, yersiniabactin (Ybt), which has been found to also bind copper and other non-iron metal ions. The observation here that an extraintestinal E. coli isolate secretes Ybt in a copper-inducible manner suggests an important gain of function over the enterobactin system. Copper recognition involves using Ybt to bind Cu(II) ions, consistent with a distinctively extracellular mode of copper detection. The resulting Cu(II)-Ybt complex signals upregulation of Ybt biosynthesis genes as a rapid response against potentially toxic extracellular copper ions. The Ybt system is distinguishable from other copper response systems that sense cytosolic and periplasmic copper ions. The Ybt dependence of the copper response presents an implicit feed-forward regulatory scheme that is typical of bacterial stress responses. The distinctive extracellular copper recognition-response functionality of the Ybt system may enhance the pathogenic potential of infection-associated Enterobacteriaceae.