PXD043757

PXD043757 is an original dataset announced via ProteomeXchange.

Title	Activation of multiple stress responses in Staphylococcus aureus substantially lowers the MIC when combining two novel antibiotic drug candidates
Description	The past few decades have been plagued by an increasing number of infections caused by antibiotic resistant bacteria. To mitigate the rise in untreatable infections, we need new antibiotics with novel targets and drug combinations that reduce resistance development. The novel β-clamp targeting antimicrobial peptide BTP-001 was recently shown to have a strong additive effect in combination with the halogenated pyrrolopyrimidine JK-274. In this study, the molecular basis for this effect was examined by a comprehensive proteomic and metabolomic study of the individual and combined effects on Staphylococcus aureus. We found that JK-274 reduced activation of several TCA cycle enzymes, likely via increasing the cellular nitric oxide stress, and BTP-001 induced oxidative stress in addition to inhibiting replication, translation, and DNA repair processes. Analysis indicated that several proteins linked to stress were only activated in the combination and not in the single treatments. These results suggest that the strong additive effect is due to the activation of multiple stress responses that can only be trigged by the combined effect of the individual mechanisms. Importantly, the combination dose required to eradicate S. aureus was well tolerated and did not affect cell viability of immortalized human keratinocyte cells. Our findings demonstrate the potential of JK-274 and BTP-001 as antibiotic drug candidates and warrant further studies.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:47:00.070.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Amanda Singleton
SpeciesList	scientific name: Staphylococcus aureus; NCBI TaxID: 1280;
ModificationList	acetylated residue; monohydroxylated residue; deamidated residue
Instrument	Bruker Daltonics timsTOF series

Revision	Datetime	Status	ChangeLog Entry
0	2023-07-13 06:02:13	ID requested
1	2023-09-13 06:41:55	announced
⏵ 2	2023-11-14 08:47:00	announced	2023-11-14: Updated project metadata.

Dataset with its publication pending

submitter keyword: antibiotics, APIM, pyrrolopyrimidine,Staphylococcus aureus

Marit Otterlei
contact affiliation	Department of Clinical and Molecular Medicine Faculty of Medicine and Health Sciences Norwegian University of Science and Technology Trondheim, Norway
contact email	marit.otterlei@ntnu.no
lab head
Amanda Singleton
contact affiliation	NTNU
contact email	amanda.singleton@ntnu.no
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD043757
     1. Label: PRIDE project
     2. Name: Activation of multiple stress responses in Staphylococcus aureus substantially lowers the MIC when combining two novel antibiotic drug candidates