Evidence map›Paper›PMID 37419898›Full record

ArticleNature communications2023

Molecular mechanism of plasmid-borne resistance to sulfonamide antibiotics.

Meenakshi Venkatesan, Michael Fruci, Lou Ann Verellen, Tatiana Skarina, Nathalie Mesa, Robert Flick, Chester Pham, Radhakrishnan Mahadevan, Peter J Stogios, Alexei Savchenko

Open access · goldAbstract read
In one paragraph

Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
62citing papers in PubMed, 1 pooled it
11.0field-weighted citation impact, top 1% 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

62 citing papers in PubMed, 1 synthesis or guideline pooled it, 115 citations in OpenAlex.

  1. Pooled it
  2. Review
  3. Article
  4. Article
  5. Article
  6. Review
  7. Article
  8. Article
  9. Article
  10. Review
  11. Mutation analysis of dihydrofolate reductase (Iranian journal of microbiology · 2026
    Article
  12. Review
  13. Article
  14. Article
  15. Metabolism-Based Biomarkers for Rapid Phenotypic Antibiotic Susceptibility Testing.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026
    Review
  16. Review
  17. Phenotypic and genomic characterization ofMicrobiology spectrum · 2026
    Article
  18. Review
  19. Article
  20. Review

2 more citing papers are in PubMed but not listed here.

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 at 3 institutions in 2 countries.

Meenakshi VenkatesanDepartment of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, M5S 1A4, Canada.ORCID 0000-0002-3673-0553
Michael FruciLondon Research and Development Centre, Agriculture and Agri-Food Canada, London, ON, N5V 4T3, Canada.
Lou Ann VerellenLondon Research and Development Centre, Agriculture and Agri-Food Canada, London, ON, N5V 4T3, Canada.
Tatiana SkarinaDepartment of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, M5S 1A4, Canada.
Nathalie MesaDepartment of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, M5S 1A4, Canada.
Robert FlickDepartment of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, M5S 1A4, Canada.
Chester PhamDepartment of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, M5S 1A4, Canada.ORCID 0000-0001-9414-589X
Radhakrishnan MahadevanDepartment of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, M5S 1A4, Canada.ORCID 0000-0002-1270-9063
Peter J StogiosDepartment of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, M5S 1A4, Canada. p.stogios@utoronto.ca.ORCID 0000-0001-8663-1425
Alexei SavchenkoDepartment of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, M5S 1A4, Canada. alexei.savchenko@ucalgary.ca.ORCID 0000-0002-5256-9237
University of Toronto · CAUniversity of Calgary · CAWestern University · CA

Funding

TO PROVIDE SCIENTIFIC SUPPORT TO THE CENTERS FOR RESEARCH ON STRUCTURAL BIOLOGY OF INFECTIOUS DISEASES.75N93022C00035 · NIAID · NORTHWESTERN UNIVERSITY AT CHICAGO · PI SATCHELL, KARLA · 2022 to 2025
$20.7M
NIAID NIH HHS 75N93022C00035NIAID NIH HHS HHSN272201700060C
6 · The paper itself

Abstract

The sulfonamides (sulfas) are the oldest class of antibacterial drugs and inhibit the bacterial dihydropteroate synthase (DHPS, encoded by folP), through chemical mimicry of its co-substrate p-aminobenzoic acid (pABA). Resistance to sulfa drugs is mediated either by mutations in folP or acquisition of sul genes, which code for sulfa-insensitive, divergent DHPS enzymes. While the molecular basis of resistance through folP mutations is well understood, the mechanisms mediating sul-based resistance have not been investigated in detail. Here, we determine crystal structures of the most common Sul enzyme types (Sul1, Sul2 and Sul3) in multiple ligand-bound states, revealing a substantial reorganization of their pABA-interaction region relative to the corresponding region of DHPS. We use biochemical and biophysical assays, mutational analysis, and in trans complementation of E. coli ΔfolP to show that a Phe-Gly sequence enables the Sul enzymes to discriminate against sulfas while retaining pABA binding and is necessary for broad resistance to sulfonamides. Experimental evolution of E. coli results in a strain harboring a sulfa-resistant DHPS variant that carries a Phe-Gly insertion in its active site, recapitulating this molecular mechanism. We also show that Sul enzymes possess increased active site conformational dynamics relative to DHPS, which could contribute to substrate discrimination. Our results reveal the molecular foundation for Sul-mediated drug resistance and facilitate the potential development of new sulfas less prone to resistance.

Indexed as

Anti-Bacterial AgentsEscherichia coli4-Aminobenzoic AcidPlasmidsSulfanilamideSulfonamides4-Aminobenzoic AcidAnti-Bacterial AgentsSulfanilamideSulfonamides

Identifiers

PMID37419898
PMCPMC10328974
OpenAlexW4383533236

What OpenQuestion holds

Textmetadata
LicenceCC BY
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.