Authors: Jeffrey Henderson (Washington University in St. Louis, MO, USA)
Take a look behind the scenes of a recent Future Microbiology paper, entitled: “The iron hand of uropathogenic E. coli: the role of transition metal control in virulence”, as we ask author Jeffrey Henderson (Washington University in St. Louis, MO, USA) about metal acquisition by uropathogenic E. coli and the future directions for this field.
What inspired you to write this review?
The alarming advance of antibiotic resistance, particularly among Gram-negative bacteria, spurs us to better understand how these troublesome organisms cause infections. Numerous lines of evidence suggest that metal ion interactions play a key role. While excellent scholarship on E.coli iron acquisition stretches back at least 40 years, there has been an abundance of recent findings concerning virulence-associated metal interactions in uropathogenic isolates. Corresponding discoveries in metal ion control by human factors help put these microbial systems into context. Many of these new advances benefited from direct analysis of clinical specimens. We felt these new observations merited an updated, disease-focused review.
What would you say has been the most breakthrough finding in the last 5 years on the topic of metal acquisition by uropathogenic E. coli?
The presence of multiple siderophore systems in uropathogenic isolates of E.coli has been regarded as an example of biological redundancy, with each of these systems involved in iron uptake. This thinking began to change when yersiniabactin, the most common non-conserved siderophore in clinical E.coli isolates, was found to bind and mediate the uptake of non-ferric metal ions, notably copper. This process also renders copper ions less toxic to E.coli. The ability to minimize copper reactivity while also mediating its controlled uptake has been termed ‘nutritional passivation’, and suggests that metals other than iron may play critical roles at the host–pathogen interface.
Can you outline the key iron acquisition systems used by uropathogenic E. coli?
We divide uropathogenic iron uptake systems into those that import uncomplexed ferrous (Fe2+) ions directly and those that import iron as complexes. These complexes may be host-derived porphyrin (heme) and citrate or bacteria-derived chelators. Uropathogenic E.coli secrete many relevant iron chelators – called siderophores – during iron-deficient growth. Enterobactin, salmochelin, aerobactin, and yersiniabactin, the four siderophores found among urinary isolates, may confer distinctive advantages in the distinct niches encountered during uropathogenesis.
Can we measure/inhibit components of these iron acquisition systems for diagnosis/ treatment of urinary tract infections?
Efforts have been made to exploit ferric siderophore importers as a means to introduce antimicrobial cargoes into bacteria – a ‘Trojan horse’ strategy. Indeed, cefiderocol, a recent entry into the antibiotic market, uses a chemical component of the E.coli siderophore enterobactin to gain access to a variety of clinical Gram-negative bacteria. Future efforts may identify other chemical groups that, by engaging other siderophore imports, direct antibiotics to a different spectrum of bacteria.
What work are you hoping to do/ what do you think needs to be done in this area?
Insights into metal interactions from E.coli are poised for comparative study in other bacterial species. Bacteria that cause UTIs and other infections likely conduct analogous metal ion interactions using different components. Understanding precisely how these mechanisms improve bacterial fitness in the present of host and microbiome-derived factors is likely to be a fruitful avenue for future study. Much remains unknown.
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