PXD021400-1

PXD021400 is an original dataset announced via ProteomeXchange.

Title	Xanthocillin X Effectively Kills A.Baumannii via Dysregulation of Heme Biosynthesis
Description	Isonitrile natural products exhibit promising antibacterial activities, however, their mode of action (MoA) remains largely unknown. Based on the nanomolar potency of xanthocillin X (Xan) against diverse difficult-to-treat Gram-negative bacteria, including the critical priority pathogen Acinetobacter baumannii, we performed in-depth studies to decipher its MoA. While neither metal binding nor cellular protein targets were relevant for Xan´s antibiotic effects, sequencing of resistant strains revealed a conserved mutation in the heme biosynthesis enzyme porphobilinogen synthase (PbgS). This mutation caused impaired enzymatic efficiency indicative of reduced heme production. This discovery led to the validation of an untapped mechanism by which direct heme sequestration of Xan prevents its binding into cognate enzyme pockets resulting in uncontrolled cofactor biosynthesis, accumulation of porphyrins and corresponding stress with deleterious effects for bacterial viability. Thus, Xan represents a promising antibiotic displaying activity even against multidrug resistant strains while exhibiting low toxicity to human cells.
HostingRepository	PRIDE
AnnounceDate	2021-09-09
AnnouncementXML	Submission_2021-09-09_09:00:54.664.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ines Hübner
SpeciesList	scientific name: Escherichia coli; NCBI TaxID: 562; scientific name: Acinetobacter baumannii ATCC 19606 = CIP 70.34 = JCM 6841; NCBI TaxID: 575584;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive HF; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2020-09-10 07:16:27	ID requested
⏵ 1	2021-09-09 09:00:55	announced

H, ü, bner I, Shapiro JA, Ho, ß, mann J, Drechsel J, Hacker SM, Rather PN, Pieper DH, Wuest WM, Sieber SA, Dysregulation of Heme Biosynthesis. ACS Cent Sci, 7(3):488-498(2021) [pubmed]

submitter keyword: Antibiotics, Isonitriles

Stephan A. Sieber
contact affiliation	Chair of Organic Chemistry II, Technical University of Munich
contact email	stephan.sieber@tum.de
lab head
Ines Hübner
contact affiliation	Technical University of Munich
contact email	ines.huebner@tum.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD021400
     1. Label: PRIDE project
     2. Name: Xanthocillin X Effectively Kills A.Baumannii via Dysregulation of Heme Biosynthesis