PXD051773-1

PXD051773 is an original dataset announced via ProteomeXchange.

Title	5-Nitroimidazole ethers boost anti-Helicobacter pylori activity via a dual mode of action and effectively eradicate infections in vivo
Description	Metronidazole (Metro) represents the front line-drug against Helicobacter pylori infections, but despite its crucial role as an antibiotic, little is known about its exact mode of action (MoA). To unravel cellular protein targets, we here performed activity-based protein profiling (ABPP) with tailored Metro probes. Surprisingly, an alkynylated ether probe (Metro-P3) exhibited a 60-fold enhanced potency against H. pylori, suggesting that this moiety represents a crucial, yet undiscovered switch for the activity profile. ABPP in living H. pylori uncovered two major protein targets, chaperonin HpGroEL and thiol peroxidase HpTpx, which are both part of the oxidative stress response and essential for H. pylori to survive under gastric oxidative stress. Tailored biological assays validated the inhibition of both targets by covalent modification of cysteines. Strikingly, the binding of Metro-P3 to HpTpx was much more pronounced compared to the parent drug. This diverging interaction of both molecules was corroborated by co-crystallization studies with Metro and Metro-P3 identifying the propargyl ether moiety to be essential for a prominent helix-dipole interaction in HpTpx. Metro-P3 along with several refined ether analogs exhibited no human cell toxicity up to 1 mM, favorable pharmacological profiles, and sufficient plasma stability. Satisfyingly, the activity boost translated to in vivo H. pylori mouse infection models where the most potent ether analog showed full eradication of bacteria at 50-fold reduced dosing compared to regular metronidazole standard triple therapy. Overall, our results highlight ether modifications of 5-nitroimidazole alcohols as unprecedented path towards dual MoA antibiotics which induce oxidative stress and simultaneously inhibit the stress response eventually leading to bacterial cell death
HostingRepository	PRIDE
AnnounceDate	2026-04-13
AnnouncementXML	Submission_2026-04-12_19:06:10.453.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Nina Bach
SpeciesList	scientific name: Helicobacter pylori 26695; NCBI TaxID: NEWT:85962;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2024-04-26 03:41:38	ID requested
⏵ 1	2026-04-12 19:06:11	announced

10.1038/s41564-026-02291-w;

Fiedler MK, Pandler MSI, Gong R, Fuchs S, Rox K, Friedrich V, Pfeiffer D, Singh D, Reinhardt T, Mibus C, Huber M, Hess CR, Mej, í, as-Luque R, Gerhard M, Groll M, Sieber SA, Metronidazole and ether derivatives target Helicobacter pylori via simultaneous stress induction and inhibition. Nat Microbiol, 11(4):1049-1063(2026) [pubmed]

submitter keyword: ABPP, full proteome,Helicobacter pylori,mode of action, nitroimidazoles, secretome, LC-MS/MS

Stephan Axel Sieber
contact affiliation	Technical University of Munich (TUM), TUM School of Natural Sciences, Department Bioscience, Chair of Organic Chemistry II, Center for Functional Protein Assemblies (CPA), Ernst-Otto-Fischer Str. 8, Garching 85748, Germany
contact email	stephan.sieber@tum.de
lab head
Nina Bach
contact affiliation	TU München
contact email	nina.bach@tum.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD051773
     1. Label: PRIDE project
     2. Name: 5-Nitroimidazole ethers boost anti-Helicobacter pylori activity via a dual mode of action and effectively eradicate infections in vivo