Evidence map›Paper›PMID 38877369›Full record

ArticleChemical biology & drug design2024

Development of phenyl-urea-based small molecules that target penicillin-binding protein 4.

Vijay S Gondil, Hailey S Butman, Mikaeel Young, Danica J Walsh, Yogesh Narkhede, Michael J Zeiler, Andrew H Crow, Morgan E Carpenter, Aashay Mardikar, Roberta J Melander and 3 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Chemical biology & drug design, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
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

4 citing papers in PubMed.

  1. Article
  2. Article
  3. Review
  4. 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.

Vijay S GondilDepartment of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA.
Hailey S ButmanDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
Mikaeel YoungDepartment of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA.
Danica J WalshDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
Yogesh NarkhedeDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
Michael J ZeilerDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
Andrew H CrowDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
Morgan E CarpenterDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
Aashay MardikarDepartment of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA.
Roberta J MelanderDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
Olaf WiestDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
Paul M DunmanDepartment of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA.
Christian MelanderDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.ORCID 0000-0001-8271-4696

Funding

Project 2: Defining the Protective vs. Susceptible Immune Proteome of S. aureus OsteomyelitisP50AR072000 · NIAMS · UNIVERSITY OF ROCHESTER · PI Edward M. Schwarz · 2017 to 2026
$13.6M
SMALL MOLECULE INHIBITORS OF CARIOGENIC BIOFILMSR01DE022350 · NIDCR · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI Christian Corey Melander, Hui Wu · 2012 to 2026
$4.3M
Antibacterial inhibitors of RnpAR01AI134685 · NIAID · UNIVERSITY OF ROCHESTER · PI DUNMAN, PAUL M. · 2018 to 2022
$3.6M
Computational and Biophysical Analysis of the Filovirus Matrix Protein SystemR01AI158220 · NIAID · PURDUE UNIVERSITY · PI STAHELIN, ROBERT VIRGIL, WIEST, OLAF G · 2021 to 2025
$3.6M
Inhibitors of adaptive efflux mediated resistance in Acinetobacter baumanniiR01AI175024 · NIAID · UNIVERSITY OF ROCHESTER · PI Paul M. Dunman, Daniel Patrick Flaherty · 2023 to 2026
$2.8M
NIAID NIH HHS R01 AI134685NIAID NIH HHS R01 AI158220NIAID NIH HHS R01 AI175024NIAMS NIH HHS P50 AR072000NIDCR NIH HHS R01 DE022350NIH HHS AI134685NIH HHS AI158220NIH HHS AI175024NIH HHS AR072000NIH HHS DE022350
6 · The paper itself

Abstract

Staphylococcus aureus has the ability to invade cortical bone osteocyte lacuno-canalicular networks (OLCNs) and cause osteomyelitis. It was recently established that the cell wall transpeptidase, penicillin-binding protein 4 (PBP4), is crucial for this function, with pbp4 deletion strains unable to invade OLCNs and cause bone pathogenesis in a murine model of S. aureus osteomyelitis. Moreover, PBP4 has recently been found to modulate S. aureus resistance to β-lactam antibiotics. As such, small molecule inhibitors of S. aureus PBP4 may represent dual functional antimicrobial agents that limit osteomyelitis and/or reverse antibiotic resistance. A high throughput screen recently revealed that the phenyl-urea 1 targets PBP4. Herein, we describe a structure-activity relationship (SAR) study on 1. Leveraging in silico docking and modeling, a set of analogs was synthesized and assessed for PBP4 inhibitory activities. Results revealed a preliminary SAR and identified lead compounds with enhanced binding to PBP4, more potent antibiotic resistance reversal, and diminished PBP4 cell wall transpeptidase activity in comparison to 1.

Indexed as

Anti-Bacterial AgentsMolecular Docking SimulationPenicillin-Binding ProteinsStaphylococcus aureusAnimalsBacterial ProteinsMiceMicrobial Sensitivity TestsSmall Molecule LibrariesStructure-Activity RelationshipUreaAnti-Bacterial AgentsBacterial ProteinsPenicillin-Binding ProteinsSAOUHSC_00646 protein, Staphylococcus aureusSmall Molecule LibrariesUreamethicillin‐resistant Staphylococcus aureusosteomyelitisPBP4phenyl‐ureaβ‐lactam

Identifiers

PMID38877369
PMCPMC11185276

What OpenQuestion holds

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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.