PXD033128

PXD033128 is an original dataset announced via ProteomeXchange.

Title	Indolin-2-one nitroimidazole antibiotics exhibit an unexpected dual mode of action
Description	Nitroimidazoles such as metronidazole are used as anti-infective drugs against anaerobic bacteria. Upon in vivo reduction of the nitro group, reactive radicals damage DNA and proteins in the absence of oxygen. Unexpectedly, a recent study of nitroimidazoles linked to an indolin-2-one substituent revealed potent activities against aerobic bacteria. This suggests a different, yet undiscovered mode of action (MoA). To decipher this MoA, we first performed whole proteome analysis of compound treated cells, revealing an upregulation of bacteriophage-associated proteins, indicative of DNA damage. Since DNA binding of the compound was not observed, we applied activity-based protein profiling (ABPP) for direct target discovery. Labeling studies revealed topoisomerase IV, an essential enzyme for DNA replication, as the most enriched hit in pathogenic Staphylococcus aureus cells. Subsequent topoisomerase assays confirmed the inhibition of DNA decatenation in the presence of indolin-2-one nitroimidazole with an activity comparable to ciprofloxacin, a known inhibitor of this enzyme. Furthermore, we determined significantly increased redox potentials of indolin-2-one nitroimidazoles compared to classic 5-nitroimidazoles such as metronidazole, which facilitates in vivo reduction. Overall, this study unravels that indolin-2-one functionalized nitroimidazoles feature an unexpected dual MoA, which impairs resistance development. Given the clinical application of this compound class, the new mechanism could be a starting point to mitigate resistance.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:31:05.510.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Nina Bach
SpeciesList	scientific name: Staphylococcus aureus; NCBI TaxID: 1280;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2022-04-08 13:52:04	ID requested
1	2022-11-09 04:05:36	announced
⏵ 2	2023-11-14 08:31:06	announced	2023-11-14: Updated project metadata.

Reinhardt T, Lee KM, Niederegger L, Hess CR, Sieber SA, Indolin-2-one Nitroimidazole Antibiotics Exhibit an Unexpected Dual Mode of Action. ACS Chem Biol, 17(11):3077-3085(2022) [pubmed]

submitter keyword: antibiotics, target-ID,ABPP

Stephan A. Sieber
contact affiliation	TU Muenchen Center for Functional Protein Assemblies Department of Chemistry Chair for Organic Chemistry II
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. PXD033128
     1. Label: PRIDE project
     2. Name: Indolin-2-one nitroimidazole antibiotics exhibit an unexpected dual mode of action