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Cited by 25Antibiotic Resistance in BacteriaBacterial Genetics and BiotechnologyAntimicrobial Resistance in Staphylococcus

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Gene amplifications cause high-level resistance against albicidin in gram-negative bacteria

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Saathoff, Mareike, Kosol, Simone, Semmler, Torsten, Tedin, Karsten, Dimos, Nicole, Kupke, Johannes, Seidel, Maria, Ghazisaeedi, Fereshteh, Jonske, Micela Condor, Wolf, Silver A., Kuropka, Benno, Czyszczoń, Wojciech, Ghilarov, Dmitry, Grätz, Stefan, Heddle, Jonathan G., Loll, Bernhard, Süssmuth, Roderich D., Fulde, Marcus·2023·PLOS Biology
DOI 10.1371/journal.pbio.3002186PMC PMC10414762

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Abstract

Antibiotic resistance is a continuously increasing concern for public healthcare. Understanding resistance mechanisms and their emergence is crucial for the development of new antibiotics and their effective use. The peptide antibiotic albicidin is such a promising candidate that, as a gyrase poison, shows bactericidal activity against a wide range of gram-positive and gram-negative bacteria. Here, we report the discovery of a gene amplification–based mechanism that imparts an up to 1000-fold increase in resistance levels against albicidin. RNA sequencing and proteomics data show that this novel mechanism protects Salmonella Typhimurium and Escherichia coli by increasing the copy number of STM3175 (YgiV), a transcription regulator with a GyrI-like small molecule binding domain that traps albicidin with high affinity. X-ray crystallography and molecular docking reveal a new conserved motif in the binding groove of the GyrI-like domain that can interact with aromatic building blocks of albicidin. Phylogenetic studies suggest that this resistance mechanism is ubiquitous in gram-negative bacteria, and our experiments confirm that STM3175 homologs can confer resistance in pathogens such as Vibrio vulnificus and Pseudomonas aeruginosa .

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Metadata

Authors
Saathoff, M., Kosol, S., Semmler, T., Tedin, K., Dimos, N., Kupke, J., Seidel, M., Ghazisaeedi, F., Jonske, M. C., Wolf, S. A., Kuropka, B., Czyszczoń, W., Ghilarov, D., Grätz, S., Heddle, J. G., Loll, B., Süssmuth, R. D., & Fulde, M.
Affiliations
  • Freie Universität Berlin (DE)
  • Technische Universität Berlin (DE)
  • Robert Koch Institute (DE)
  • Jagiellonian University (PL)
Corresponding author
  • Süssmuth, Roderich D.
  • Fulde, Marcus
ORCID
Venue
PLOS Biology
Publisher
Public Library of Science (PLoS)
Published
2023-08-10
Volume
21
Issue
8
Pages
e3002186
ISSN
  • 1544-9173 (ISSN-L)
  • 1545-7885
DOI
10.1371/journal.pbio.3002186
PMC
PMC10414762
OpenAlex
W4385727347
Cited by
25
References
3
Citations by year
2026: 2 · 2025: 10 · 2024: 8 · 2023: 5
FWCI
2.11
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Homo Politicus (Academy of Humanities and Economics in Lodz) (submittedVersion, cc-by-nc-nd)
  • Publication server of the Robert Koch Institute (Robert Kock Institute) (submittedVersion, cc-by)
  • Refubium (Universitätsbibliothek der Freien Universität Berlin) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • HZB Repository (Helmholtz-Zentrum Berlin für Materialien und Energie GmbH (HZB)) (submittedVersion, other-oa)
  • Universitätsbibliothek der FU Berlin Hochschulschriftenstelle u. Dokumentenserver (cc-by)
Funders
  • Deutsche Forschungsgemeinschaft (SU 239/18-1, priority program SPP2225 (FU 1027/4-1), CRC 1449; Project ID 431232613; project B5)
  • H. Wilhelm Schaumann Stiftung (scholarship)
  • Freie Universität Berlin
  • Narodowym Centrum Nauki (2020/39/B/NZ1/02898 (OPUS 20))
Topics
  • Health Sciences › Medicine › Microbiology (medical) › Antibiotic Resistance in Bacteria
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
Keywords
albicidin, antibiotic resistance, gene amplification, transcription regulators, Salmonella typhimurium, Escherichia coli, Vibrio vulnificus, Pseudomonas aeruginosa, Gram-negative bacteria
MeSH terms
Anti-Bacterial Agents, Gene Amplification, Gram-Negative Bacteria, Gram-Positive Bacteria, Organic Chemicals, Phylogeny, Xanthomonas, Molecular Docking Simulation

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