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PXD027810

PXD027810 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleTargeting the fitness cost of antibiotic resistance via the non-essential genome
DescriptionMutations in the rifampicin (Rif)-binding site of RNA polymerase (RNAP) impart antibiotic resistance and inextricably affect transcription initiation, elongation, and termination properties as well. At each step of the transcription cycle, RNAP responds to non-essential transcription factors, signaling molecules, and substrate availability. As such, the non- essential genome and its impact on fitness cost potentially represent an untapped resource for new combination therapies. Using transposon sequencing (Tn-seq), we present a genome- wide analysis of resistance cost in a clinically common rpoB H526Y mutant. Our data show that cost-compounding genes include factors that promote high transcription elongation rate, whereas cost-mitigating genes function in cell wall synthesis and division. We demonstrate that cell wall synthesis and division defects in rpoB H526Y are a consequence of an abnormally high transcription elongation rate, which is further exacerbated by superfluous activity of the uracil salvage pathway and indifference of the mutant RNAP to alarmone ppGpp. Leveraging on this knowledge, we identified drugs that are highly potent against rpoB H526Y and other RifR alleles from the same phenotypic class. Thus, genome-wide analysis of fitness cost of antibiotic resistant mutants should expedite discovery of new combination therapies and delineate cellular pathways that underlie molecular mechanisms of cost.
HostingRepositoryPRIDE
AnnounceDate2021-11-25
AnnouncementXMLSubmission_2021-11-25_07:46:18.573.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterNikita Vasilyev
SpeciesList scientific name: Escherichia coli; NCBI TaxID: 562;
ModificationListacetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
InstrumentOrbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02021-08-09 06:33:49ID requested
12021-11-25 07:46:19announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: antibiotic resistance, rifampicin, RNA polymerase, fitness cost
Contact List
Evgeny Nudler
contact affiliationDepartment of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, US
contact emailevgeny.nudler@nyulangone.org
lab head
Nikita Vasilyev
contact affiliationNYU School of Medicine
contact emailnikita.vasilyev@nyulangone.org
dataset submitter
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Dataset FTP location
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