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NIH grant 1F31AI189082-01: Yersiniabactin Precursor Escherichelin May Enhance Enterobacteriaceae Colonization and Pathogenicity in Inflamed Colon
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Felix Anthony Argueta. Award: $43097.
Start: 2026-10-16T00:00:00.
Project Summary.
Microbial competition is a complex process that can act to protect the host from infection by pathogens. Probiotic
Escherichia coli Nissle 1917 (EcN) competes with Salmonella enterica serovar Typhimurium (STm) using several
strategies that include iron acquisition via siderophores and secretion of small antimicrobial proteins called
microcins. Whether EcN also competes with STm and other pathogens for other metal nutrients, including zinc,
is not well understood. The yersiniabactin gene cluster is a biosynthesis pathway that synthesizes and secretes
yersiniabactin (Ybt), a metallophore originally described in Yersinia pestis. Ybt is found in a range of pathogenic
Enterobacteriaceae, including E. coli. Adherent-invasive E. coli (AIEC) is a distinct and virulent pathovar
associated with IBD and is a Ybt producer. Ybt is internalized via the outer membrane permease FyuA, and the
inner membrane permease YbtX. The Ybt gene cluster expresses two main proteins: HMWP2 (encoded by irp2)
and HMWP1 (encoded by irp1), where HMWP2 is upstream of HMWP1 and creates the Ybt precursor and small
molecule metabolite HPTT-COOH, also termed escherichelin. It is unknown whether escherichelin contributes
to growth and metal competition. Our central hypothesis is that escherichelin functions as a zincophore,
contributing to Zn acquisition in commensal and pathogenic E. coli. In the case of EcN, we hypothesize that
escherichelin production will provide a competitive advantage against STm during colitis. In the case of AIEC,
we hypothesize that escherichelin will enhance colonization of this pathobiont, potentially exacerbating colitis.
To address this knowledge gap, various knockouts will be created. To test this hypothesis my first aim is to use
extracted escherichelin and the irp1 and irp2 mutants to elucidate whether escherichelin functions as a
zincophore in vitro and in vivo. The growth advantage of escherichelin will be assessed in vivo by using a murine
model of colitis. Next, growth curves will be performed in different media to measure the growth response when
zinc is present. Additionally, a second aim will determine whether zinc acquisition via escherichelin enables EcN
to compete with STm in the inflamed gut and in vitro. To answer this, mice will be co-infected with the EcN irp1
mutant and STm. Additionally, to investigate whether escherichelin boosts pathogenesis, AIEC infections with
irp mutants will be performed. The outcome of this research will inform on metal competition in the gut during
infection and inflammation and is necessary to understand potential microbe-based treatments and prophylaxis.document fetched 2026-10-24 02:46