PXD025088

PXD025088 is an original dataset announced via ProteomeXchange.

Title	Polymyxin resistance in colibactin-producing Escherichia coli induces host genotoxicity
Description	The complex reservoir of metabolite-producing bacteria in the gastrointestinal tract contributes tremendously to human health and disease. Bacterial composition, and by extension gut metabolomic composition, is undoubtably influenced by the use of modern antibiotics. Herein, we demonstrate that polymyxin B, a last resort antibiotic used for chronic multidrug resistant infections infections, influences the production of the genotoxic metabolite colibactin from adherent-invasive Escherichia coli (AIEC) NC101. Colibactin can augment colorectal cancer (CRC) through DNA double stranded breaks and interstrand crosslinks. While the structure and biosynthesis of colibactin has been elucidated, chemical-induced regulation of its biosynthetic gene cluster and subsequent production of the genotoxin by pathogenic E. coli are largely unexplored. This research highlights the regulation of the colibactin-producing biosynthetic gene cluster under polymyxin stress. Using a multi-omic approach, we have identified that polymyxin stress enhances the abundance of colibactin biosynthesis proteins (Clb’s) in multiple pks+ E. coli strains, including pro-carcinogenic AIEC: NC101, the probiotic strain: E. coli Nissle 1917, and the antibiotic testing strain: E. coli ATCC 25922. Expression analysis via qPCR revealed that increased transcription of clb genes likely contributes to elevated Clb protein levels in NC101. Enhanced production of Clb’s by NC101 under polymyxin stress matched an increased production of the colibactin prodrug motif, a proxy for the mature genotoxic metabolite. Furthermore, E. coli with heightened tolerance for polymyxin antibiotics induced greater DNA damage, assessed by quantification of γH2AX staining in cultured intestinal epithelial cells. This study establishes a key link between the polymyxin B stress response and colibactin production in pks+ E. coli. Ultimately, our findings will inform future studies investigating colibactin regulation, the microbial response to antibiotics in the gut, and the ability of seemingly innocuous commensal microbes to induce host disease.
HostingRepository	PRIDE
AnnounceDate	2021-07-16
AnnouncementXML	Submission_2021-07-15_23:06:08.137.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD025088
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Leslie Hicks
SpeciesList	scientific name: Escherichia coli; NCBI TaxID: 562;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2021-03-29 12:23:12	ID requested
1	2021-07-15 14:25:39	announced
⏵ 2	2021-07-15 23:06:09	announced	2021-07-16: Updated project metadata.

Sadecki PW, Balboa SJ, Lopez LR, Kedziora KM, Arthur JC, Hicks LM, . ACS Chem Biol, 16(7):1243-1254(2021) [pubmed]

10.1021/ACSCHEMBIO.1C00322;

submitter keyword: Escherichia coli,Colibactin, antimicrobial resistance

Leslie M. Hicks
contact affiliation	University of North Carolina at Chapel Hill - Department of Chemistry
contact email	lmhicks@unc.edu
lab head
Leslie Hicks
contact affiliation	University of North Carolina at Chapel Hill
contact email	lmhicks@unc.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD025088
     1. Label: PRIDE project
     2. Name: Polymyxin resistance in colibactin-producing Escherichia coli induces host genotoxicity