Dataset Information

Indolin-2-one nitroimidazole antibiotics exhibit an unexpected dual mode of action

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion, Q Exactive

ORGANISM(S): Staphylococcus Aureus

SUBMITTER: Nina Bach

LAB HEAD: Stephan A. Sieber

PROVIDER: PXD033128 | Pride | 2022-11-09

REPOSITORIES: pride

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Dataset's files

Source:

			Action	DRS
	ABPP_Competition.zip	Other
	ABPP_Dosedown.zip	Other
	FASTA_S_aureus_NCTC8325_UP000008816_13052021_2889entries.fasta	Fasta
	Full_Proteome_Analysis.zip	Other
	mqpar_ABPP_Competition.xml	Xml

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Publications

Indolin-2-one Nitroimidazole Antibiotics Exhibit an Unexpected Dual Mode of Action.

Reinhardt Till T Lee Kyu M KM Niederegger Lukas L Hess Corinna R CR Sieber Stephan A SA

ACS chemical biology 20221019 11

Nitroimidazoles such as metronidazole are used as anti-infective drugs against anaerobic bacteria. Upon <i>in vivo</i> 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- ...[more]

PMID: 36259427

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