Evidence map›Paper›PMID 39732052›Full record

ArticleCell chemical biology2025

Discovery of a Pseudomonas aeruginosa-specific small molecule targeting outer membrane protein OprH-LPS interaction by a multiplexed screen.

Bradley E Poulsen, Thulasi Warrier, Sulyman Barkho, Josephine Bagnall, Keith P Romano, Tiantian White, Xiao Yu, Tomohiko Kawate, Phuong H Nguyen, Kyra Raines and 8 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell chemical biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing 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

6 citing papers in PubMed.

  1. Article
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  5. Article
  6. Perturbation-specific transcriptional mapping for unbiased target elucidation of antibiotics.Proceedings of the National Academy of Sciences of the United States of America · 2024
    Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

18 authors.

Bradley E PoulsenDepartment of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Thulasi WarrierDepartment of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Sulyman BarkhoBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Josephine BagnallBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Keith P RomanoDepartment of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Tiantian WhiteDepartment of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Xiao YuDepartment of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Tomohiko KawateDepartment of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Phuong H NguyenDepartment of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Kyra RainesDepartment of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Kristina FerraraDepartment of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
A Lorelei GolasBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Michael FitzGeraldBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Andras BoeszoermenyiBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Virendar KaushikBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA; 3 Point Bio LLC, Cambridge, MA 02142, USA.
Michael Serrano-Wu3 Point Bio LLC, Cambridge, MA 02142, USA.
Noam ShoreshBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Deborah T HungDepartment of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: hung@molbio.mgh.harvard.edu.

Funding

Innovative technologies to transform antibiotic discovery. Project 4 Infection site-specific amplification of antimicrobial conjugatesU19AI142780 · NIAID · BROAD INSTITUTE, INC. · PI HUNG, DEBORAH T · 2019 to 2023
$33.9M
Multiplexed targeting of Pseudomonas aeruginosa essential outer membrane proteinsR33AI098705 · NIAID · MASSACHUSETTS GENERAL HOSPITAL · PI HUNG, DEBORAH T · 2014 to 2016
$1.3M
Multiplexed targeting of Pseudomonas aeruginosa essential outer membrane proteinsR21AI098705 · NIAID · MASSACHUSETTS GENERAL HOSPITAL · PI HUNG, DEBORAH T · 2012 to 2013
$476k
NIAID NIH HHS R21 AI098705NIAID NIH HHS R33 AI098705NIAID NIH HHS U19 AI142780
6 · The paper itself

Abstract

The surge of antimicrobial resistance threatens efficacy of current antibiotics, particularly against Pseudomonas aeruginosa, a highly resistant gram-negative pathogen. The asymmetric outer membrane (OM) of P. aeruginosa combined with its array of efflux pumps provide a barrier to xenobiotic accumulation, thus making antibiotic discovery challenging. We adapted PROSPECT, a target-based, whole-cell screening strategy, to discover small molecule probes that kill P. aeruginosa mutants depleted for essential proteins localized at the OM. We identified BRD1401, a small molecule that has specific activity against a P. aeruginosa mutant depleted for the essential lipoprotein, OprL. Genetic and chemical biological studies identified that BRD1401 acts by targeting the OM β-barrel protein OprH to disrupt its interaction with LPS and increase membrane fluidity. Studies with BRD1401 also revealed an interaction between OprL and OprH, directly linking the OM with peptidoglycan. Thus, a whole-cell, multiplexed screen can identify species-specific chemical probes to reveal pathogen biology.

Indexed as

Anti-Bacterial AgentsBacterial Outer Membrane ProteinsDrug DiscoveryLipopolysaccharidesPseudomonas aeruginosaSmall Molecule LibrariesMicrobial Sensitivity TestsAnti-Bacterial AgentsBacterial Outer Membrane ProteinsLipopolysaccharidesSmall Molecule Librarieschemical screeninggram-negative bacteriagrowth inhibitorlipopolysaccharideLPSOprHouter membranePseudomonas aeruginosaTol-Pal

Identifiers

PMID39732052
PMCPMC12117999

What OpenQuestion holds

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Registered trials

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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.