Siderophore Immunization Restricted Colonization of Adherent-Invasive Escherichia coli and Ameliorated Experimental Colitis

Gerner, Romana R.; Hossain, Suzana; Sargun, Artur; Siada, Kareem; Norton, Grant J.; Zheng, Teng‐Fei; Neumann, Wilma; Nuccio, Sean Paul; Nolan, Elizabeth M.; Raffatellu, Manuela

doi:10.1128/mbio.02184-22

Cited by 14 publications

(9 citation statements)

References 72 publications

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“…In accord with this, host immunization with siderophore-based vaccines was shown to elicit a strong mucosal immune response that can quell AIEC expansion and decrease gut inflammation. 104 Taken together, these results underpin the potential of targeting iron acquisition systems as a strategy to complement the host nutritional immunity against CD-associated pathogens.…”

Section: Metabolic Adaptation Of Aiecmentioning

confidence: 93%

The multifaceted virulence of adherent-invasive Escherichia coli

2023

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The surge in inflammatory bowel diseases, like Crohn’s disease (CD), is alarming. While the role of the gut microbiome in CD development is unresolved, the frequent isolation of adherent-invasive Escherichia coli (AIEC) strains from patient biopsies, together with their propensity to trigger gut inflammation, underpin the potential role of these bacteria as disease modifiers. In this review, we explore the spectrum of AIEC pathogenesis, including their metabolic versatility in the gut. We describe how AIEC strains hijack the host defense mechanisms to evade immune attrition and promote inflammation. Furthermore, we highlight the key traits that differentiate AIEC from commensal E. coli . Deciphering the main components of AIEC virulence is cardinal to the discovery of the next generation of antimicrobials that can selectively eradicate CD-associated bacteria.

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Section: Metabolic Adaptation Of Aiecmentioning

confidence: 93%

The multifaceted virulence of adherent-invasive Escherichia coli

2023

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“…53−55 Over the past decade, we have collaborated with the Raffatellu laboratory on developing Ent-based immunization as a strategy to combat Gram-negative bacterial infections. 53,55 We immunized mice with conjugates of Ent and the mucosal adjuvant cholera toxin subunit B (CTB-Ent 32, Figure 7), which caused the mice to develop anti-Ent and anti-DGE antibodies in the gut mucosa. To date, we have examined the consequences of CTB-Ent immunization in two murine models, a Salmonella infection model and an adherent-invasive E. coli colitis model; in both cases the immunization was protective.…”

Section: Other Applications Of the Monofunctionalized Ent Scaffoldsmentioning

confidence: 99%

“…Fluorescent conjugate Ent-coumarin 29 was employed by others to visualize the periplasmic accumulation of Ent in an E. coli tolC mutant, which lacks the OM component of tripartite efflux pumps . Biotinylated conjugate Ent-biotin 30 was used by ourselves and others to identify Ent-interacting proteins, furthering our understanding of the role of Ent in host–microbe and microbe–microbe interactions. − Over the past decade, we have collaborated with the Raffatellu laboratory on developing Ent-based immunization as a strategy to combat Gram-negative bacterial infections. , We immunized mice with conjugates of Ent and the mucosal adjuvant cholera toxin subunit B (CTB-Ent 32 , Figure ), which caused the mice to develop anti-Ent and anti-DGE antibodies in the gut mucosa. To date, we have examined the consequences of CTB-Ent immunization in two murine models, a Salmonella infection model and an adherent-invasive E. coli colitis model; in both cases the immunization was protective.…”

Section: Other Applications Of the Monofunctionalized Ent Scaffoldsmentioning

confidence: 99%

Exploring the Antibacterial Activity and Cellular Fates of Enterobactin–Drug Conjugates That Target Gram-Negative Bacterial Pathogens

Guo,

Nolan

2024

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations * sı Supporting Information CONSPECTUS: Siderophores are secondary metabolites utilized by bacteria to acquire iron (Fe), an essential transition metal nutrient. Fe levels in the host environment are tightly regulated and can be further restricted to starve invading bacterial pathogens in a host-defense process known as nutritional immunity. To survive and colonize the Fe-limited host environment, bacteria produce siderophores and express cognate siderophore transport machinery. These active transport pathways present an opportunity for selective and efficient drug delivery into bacterial cells, motivating decades of research on synthetic siderophore−antibiotic conjugates (SACs) as a Trojan-horse strategy for the development of targeted antibiotics. Enterobactin (Ent) is a triscatecholate siderophore produced and utilized by many Gram-negative bacteria, including all Escherichia coli and Salmonella species. Within these species, pathogenic strains cause a variety of human diseases including urinary tract infections, gastroenteritis, and sepsis. Infections caused by these Gram-negative pathogens can be difficult to treat because of the impermeability of the outer membrane (OM). This impermeability can be overcome by utilizing siderophores as drug delivery vectors for targeting Gram-negative pathogens. Ent is a promising delivery vector because it undergoes active transport across the OM mediated by the Ent uptake machinery after scavenging Fe(III) from the extracellular environment. Despite the well-elucidated chemistry and biology of Ent, its use for SAC development was hampered by the lack of an appropriate functional group for cargo attachment. Our laboratory addressed this need by designing and synthesizing monofunctionalized Ent scaffolds. Over the past decade, we have used these scaffolds to explore Ent-based SACs with a variety of drug warheads, including β-lactam and fluoroquinolone antibiotics, and Pt(IV) prodrugs. Investigations of the antibacterial activities of these conjugates and their cellular fates have informed our design principles and revealed approaches to achieving enhanced antibacterial potency and pathogentargeted activity. Collectively, our studies of Ent−drug conjugates have provided discoveries, understanding, and invaluable insights for future design and evaluation of SACs.In this Account, we present the story of our work on Ent−drug conjugates that began about ten years ago with the development of monofunctionalized Ent scaffolds and the design and synthesis of various conjugates based on these scaffolds. We describe the antibacterial activity profiles and uptake pathways of Ent−drug conjugates harboring traditional antibiotics and repurposed platinum anticancer agents as well as studies that address cellular targets and fates. Finally, we discuss other applications of monofunctionalized Ent scaffolds, including a siderophore-based immunization strategy. We intend for this Account to inspire further investigations into the fundamental understanding ...

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“…12 In addition, colibactin triggers prophage induction 13 and shapes the enteric microbiome through species-specic interactions. 14 Streptosactin (12), which is produced by the gut commensal Streptococcus thermophilus, is the rst reported sactipeptide with potent antibacterial activity. 15 Enterobactin (13), besides serving as a siderophore and virulence factor in the gut, was reported to increase mitochondrial iron uptake by binding with the mitochondrial ATP synthase alpha subunit, thus promoting Caenorhabditis elegans development.…”

Section: Gut Microbiota-derived and Biologically Active Npsmentioning

confidence: 99%