Evidence map›Paper›PMID 28160417›Full record

ArticleChemical biology & drug design2017

NMR structure-based optimization of Staphylococcus aureus sortase A pyridazinone inhibitors.

Albert H Chan, Sung Wook Yi, Ethan M Weiner, Brendan R Amer, Christopher K Sue, Jeff Wereszczynski, Carly A Dillen, Silvia Senese, Jorge Z Torres, J Andrew McCammon and 3 more

Open access · greenAbstract readEditorial
PubMed Full text at PMC Publisher
In one paragraph

Article in Chemical biology & drug design, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.

0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed
1.0field-weighted citation impact, top 25% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

9 citing papers in PubMed, 21 citations in OpenAlex.

  1. Review
  2. The Discovery of Novel Agents againstPharmaceuticals (Basel, Switzerland) · 2023
    Article
  3. Covalent sortase A inhibitor ML346 preventsRSC medicinal chemistry · 2022
    Article
  4. Review
  5. Article
  6. Article
  7. Article
  8. Design and Synthesis of Small Molecules as PotentAntibiotics (Basel, Switzerland) · 2020
    Review
  9. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors at 4 institutions in 1 country.

Albert H ChanDepartment of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA.ORCID http://orcid.org/0000-0001-5809-8483
Sung Wook YiDepartment of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA.
Ethan M WeinerDepartment of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA.
Brendan R AmerDepartment of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA.
Christopher K SueDepartment of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA.
Jeff WereszczynskiDepartment of Physics and Center for Molecular Study of Condensed Soft Matter, Illinois Institute of Technology, Chicago, IL, USA.
Carly A DillenDepartment of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Silvia SeneseDepartment of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA.
Jorge Z TorresDepartment of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA.
J Andrew McCammonDepartment of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.
Lloyd S MillerDepartment of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Michael E JungDepartment of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA.
Robert T ClubbDepartment of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA.
University of California, Los Angeles · USJohns Hopkins University · USHoward Hughes Medical Institute · USIllinois Institute of Technology · US

Funding

National Biomedical Computation Resource - Competitive Revision SupplementP41GM103426 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI AMARO, ROMMIE E · 2012 to 2019
$14.0M
Cell Surface Protein Anchoring in Gram-Positive BacteriaR01AI052217 · NIAID · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Robert Thompson Clubb · 2002 to 2026
$8.5M
THEORY OF BIOMOLECULAR DIFFUSIONR01GM031749 · NIGMS · UNIVERSITY OF HOUSTON · PI HUBER, GARY ALEXANDER, MCCAMMON, JAMES ANDREW · 1985 to 2022
$7.8M
CHEMISTRY BIOLOGY INTERFACE TRAINING PROGRAMT32GM008496 · NIGMS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI MAYNARD, HEATHER D · 1993 to 2019
$6.3M
Bruker Avance III Console and QCI Cryoprobe for a 600 MHz NMR SpectrometerS10OD016336 · OD · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI CLUBB, ROBERT THOMPSON · 2014 to 2014
$600k
Time-of-Flight Mass Spectrometer for Synthesis Supporting Biomedical ResearchS10RR025631 · NCRR · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI HOUK, KENDALL N · 2009 to 2009
$328k
NCRR NIH HHS S10 RR025631NIAID NIH HHS R01 AI052217NIGMS NIH HHS P41 GM103426NIGMS NIH HHS R01 GM031749NIGMS NIH HHS T32 GM008496NIH HHS S10 OD016336
6 · The paper itself

Abstract

Staphylococcus aureus is a leading cause of hospital-acquired infections in the USA and is a major health concern as methicillin-resistant S. aureus and other antibiotic-resistant strains are common. Compounds that inhibit the S. aureus sortase (SrtA) cysteine transpeptidase may function as potent anti-infective agents as this enzyme attaches virulence factors to the bacterial cell wall. While a variety of SrtA inhibitors have been discovered, the vast majority of these small molecules have not been optimized using structure-based approaches. Here we have used NMR spectroscopy to determine the molecular basis through which pyridazinone-based small molecules inhibit SrtA. These inhibitors covalently modify the active cysteine thiol and partially mimic the natural substrate of SrtA by inducing the closure of an active site loop. Computational and synthetic chemistry methods led to second-generation analogues that are ~70-fold more potent than the lead molecule. These optimized molecules exhibit broad-spectrum activity against other types of class A sortases, have reduced cytotoxicity, and impair SrtA-mediated protein display on S. aureus cell surface. Our work shows that pyridazinone analogues are attractive candidates for further development into anti-infective agents, and highlights the utility of employing NMR spectroscopy and solubility-optimized small molecules in structure-based drug discovery.

Indexed as

AminoacyltransferasesAnti-Bacterial AgentsBacterial ProteinsBinding SitesCatalytic DomainCell SurvivalCell WallCysteine EndopeptidasesEnzyme InhibitorsFluorescence Resonance Energy TransferHeLa CellsHumansKineticsMagnetic Resonance SpectroscopyMass SpectrometryMolecular ConformationAminoacyltransferasesAnti-Bacterial AgentsBacterial ProteinsCysteine EndopeptidasesEnzyme InhibitorsPyridazinessortase Amolecular dockingmolecular dynamicsNMRprotein-inhibitor complexprotein structureSortaseSrtAStaphylococcus aureustranspeptidase

Identifiers

PMID28160417
PMCPMC5540818
OpenAlexW2584637434

What OpenQuestion holds

Textmetadata
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Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.