Evidence map›Paper›PMID 36715507›Full record

ArticleAntimicrobial agents and chemotherapy2023

Functional Diversity of Gram-Negative Permeability Barriers Reflected in Antibacterial Activities and Intracellular Accumulation of Antibiotics.

Inga V Leus, Justyna Adamiak, Brinda Chandar, Vincent Bonifay, Shibin Zhao, Scott S Walker, Brian Squadroni, Carl J Balibar, Nihar Kinarivala, Lisa C Standke and 4 more

Open access · greenAbstract read
In one paragraph

Article in Antimicrobial agents and chemotherapy, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.

0numbers the graph read from it
0cells of the map it votes in
31citing papers in PubMed
3.9field-weighted citation impact, top 5% 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

31 citing papers in PubMed, 41 citations in OpenAlex.

  1. Article
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  14. No two are alike: on the role ofAntimicrobial agents and chemotherapy · 2025
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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

14 authors at 4 institutions in 1 country.

Inga V LeusDepartment of Chemistry & Biochemistry, University of Oklahoma, Norman, Oklahoma, USA.
Justyna AdamiakDepartment of Chemistry & Biochemistry, University of Oklahoma, Norman, Oklahoma, USA.
Brinda ChandarDepartment of Chemistry & Biochemistry, University of Oklahoma, Norman, Oklahoma, USA.
Vincent BonifayDepartment of Chemistry & Biochemistry, University of Oklahoma, Norman, Oklahoma, USA.
Shibin ZhaoChemical Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Scott S WalkerMerck & Co., Inc., Rahway, New Jersey, USA.
Brian SquadroniMerck & Co., Inc., Rahway, New Jersey, USA.
Carl J BalibarMerck & Co., Inc., Rahway, New Jersey, USA.
Nihar KinarivalaChemical Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Lisa C StandkePharmacology Program, Weill Cornell Graduate School of Medical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Henning U VossCornell MRI Facility, Cornell University, Ithaca, New York, USA.
Derek S TanChemical Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Valentin V RybenkovDepartment of Chemistry & Biochemistry, University of Oklahoma, Norman, Oklahoma, USA.ORCID 0000-0002-5300-4369
Helen I ZgurskayaDepartment of Chemistry & Biochemistry, University of Oklahoma, Norman, Oklahoma, USA.ORCID 0000-0001-8929-4727
University of Oklahoma · USMemorial Sloan Kettering Cancer Center · USMerck & Co., Inc., Rahway, NJ, USA (United States) · USCornell University · US

Funding

X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI SELWYN M VICKERS · 1985 to 2026
$347.4M
Predictive Models for Small-Molecule Accumulation in Gram-Negative BacteriaR01AI136795 · NIAID · SLOAN-KETTERING INST CAN RESEARCH · PI TAN, DEREK S, ZGURSKAYA, HELEN I · 2018 to 2022
$6.5M
Permeability Barriers of Gram-negative Pathogens and Approaches to Bypass ThemR01AI132836 · NIAID · UNIVERSITY OF OKLAHOMA · PI HELEN I ZGURSKAYA · 2017 to 2026
$4.3M
Predoctoral Training in Pharmacological SciencesT32GM073546 · NIGMS · WEILL MEDICAL COLL OF CORNELL UNIV · PI GROSS, STEVEN S · 2006 to 2020
$3.1M
Development of Pharmacologically Optimized Inhibitors of M. tuberculosis MbtA as Novel AntibioticsF31AI129244 · NIAID · WEILL MEDICAL COLL OF CORNELL UNIV · PI STANDKE, LISA CHARLOTTE · 2017 to 2019
$134k
NCI NIH HHS P30 CA008748NIAID NIH HHS F31 AI129244NIAID NIH HHS R01 AI132836NIAID NIH HHS R01 AI136795NIGMS NIH HHS T32 GM073546
6 · The paper itself

Abstract

Gram-negative bacteria are notoriously more resistant to antibiotics than Gram-positive bacteria, primarily due to the presence of the outer membrane and a plethora of active efflux pumps. However, the potency of antibiotics also varies dramatically between different Gram-negative pathogens, suggesting major mechanistic differences in how antibiotics penetrate permeability barriers. Two approaches are used broadly to analyze how permeability barriers affect intracellular accumulation of antibiotics. One compares the antibacterial activities of compounds, while the other measures the total intracellular concentrations of compounds in nongrowing cells, with both approaches using strains harboring wild-type or genetically modified efflux systems and permeability barriers. Whether the two assays provide similar mechanistic insights remains unclear. In this study, we analyzed the intracellular accumulation and antibacterial activities of antibiotics representative of major clinical classes in three Gram-negative pathogens of high clinical importance, Pseudomonas aeruginosa, Escherichia coli, and Acinetobacter baumannii. We found that both assays are informative about properties of permeability barriers, but there is no quantitative agreement between the assays. Our results show that the three pathogens differ dramatically in their permeability barriers, with the outer membrane playing the dominant role in E. coli and P. aeruginosa but efflux dominating in A. baumannii. However, even compounds of the same chemotype may use different permeation pathways depending on small chemical modifications. Accordingly, a classification analysis revealed limited conservation of molecular properties that define compound penetration into the three bacteria.

Indexed as

Anti-Bacterial AgentsEscherichia coliBiological TransportGram-Negative BacteriaMicrobial Sensitivity TestsPermeabilityPseudomonas aeruginosaAnti-Bacterial Agentsantibiotic resistancedrug permeationGram-negative bacteriamultidrug efflux

Identifiers

PMID36715507
PMCPMC9933635
OpenAlexW4318482194

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.