Evidence map›Paper›PMID 42248056›Full record

ArticleEuropean journal of medicinal chemistry2026

IMD-0354 optimization generates potent colistin adjuvants with in vivo activity and reduced eukaryotic toxicity.

Luke J Cowart, Ansley M Nemeth, Leigh A Jania, Moira Overly, Courtney F Ellis, Beverly H Koller, Roberta J Melander, Yohei Doi, Robert K Ernst, Christian Melander

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in European journal of medicinal chemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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

10 authors.

Luke J CowartDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.
Ansley M NemethDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.
Leigh A JaniaDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Moira OverlyDepartment of Microbial Pathogenesis, University of Maryland School of Dentistry, Baltimore, MD, USA.
Courtney F EllisDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.
Beverly H KollerDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Roberta J MelanderDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.
Yohei DoiCenter for Innovative Antimicrobial Therapy, Division of Infectious Diseases, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Robert K ErnstDepartment of Microbial Pathogenesis, University of Maryland School of Dentistry, Baltimore, MD, USA.
Christian MelanderDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA. Electronic address: cmelande@nd.edu.

Funding

Colistin-resistant Acinetobacter baumanniiR01AI104895 · NIAID · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI DOI, YOHEI, ERNST, ROBERT K · 2014 to 2024
$4.2M
Development of Antibiotic Adjuvants for Gram-Negative BacteriaR01AI136904 · NIAID · UNIVERSITY OF NOTRE DAME · PI MELANDER, CHRISTIAN COREY · 2018 to 2022
$3.7M
Repurposing Gram-positive Antibiotics for Gram-Negative Bacteria using Antibiotic AdjuvantsR01AI167284 · NIAID · UNIVERSITY OF NOTRE DAME · PI MELANDER, CHRISTIAN COREY · 2022 to 2025
$3.7M
Chemistry-Biochemistry-Biology Interface (CBBI) Program at Notre DameT32GM145773 · NIGMS · UNIVERSITY OF NOTRE DAME · PI Christian Corey Melander · 2022 to 2026
$1.5M
NIAID NIH HHS R01 AI104895NIAID NIH HHS R01 AI136904NIAID NIH HHS R01 AI167284NIGMS NIH HHS T32 GM145773
6 · The paper itself

Abstract

The development of novel therapeutic approaches to combat infections that stem from extensively drug-resistant (XDR) gram-negative bacteria remains an area of significant unmet need. One such approach is the use of antibiotic adjuvants. Currently, colistin (polymyxin E) is used as the antibiotic of last resort for the treatment of XDR gram-negative bacterial infections. However, resistance to this antibiotic is on the rise. We previously reported that IMD-0354 (an IκB kinase-β inhibitor) and related salicylanilide adjuvants overcome colistin resistance in several gram-negative pathogens. However, this scaffold exhibits unfavorable eukaryotic toxicity, thought to arise from the salicyl moiety. Herein, we investigate the structure-activity relationship (SAR) of second-generation m-hydroxybenzanilide analogs of IMD-0354, to uncover compounds with reduced eukaryotic toxicity and IκB kinase-β inhibitory properties, while maintaining colistin adjuvant activity. We have identified new leads that lower the colistin minimum inhibitory concentration (MIC) upwards of 2048-fold against highly colistin-resistant Acinetobacter baumannii and Klebsiella pneumoniae. In particular, NDM-622 exhibits reduced HepG2 toxicity compared to IMD-0354, with an IC

Indexed as

Anti-Bacterial AgentsBenzamidesColistinAcinetobacter baumanniiAnimalsDose-Response Relationship, DrugDrug Resistance, BacterialHep G2 CellsHumansI-kappa B KinaseKlebsiella pneumoniaeMiceMicrobial Sensitivity TestsMolecular StructureStructure-Activity RelationshipAnti-Bacterial AgentsBenzamidesColistinI-kappa B Kinase

Identifiers

PMID42248056
PMCPMC13479383

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.