Gene amplifications cause high-level resistance against albicidin in gram-negative bacteria.
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...
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Public Library of Science (PLoS)
2023-08-01
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| Series: | PLoS Biology |
| Online Access: | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3002186&type=printable |
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| author | Mareike Saathoff Simone Kosol Torsten Semmler Karsten Tedin Nicole Dimos Johannes Kupke Maria Seidel Fereshteh Ghazisaeedi Micela Condor Jonske Silver A Wolf Benno Kuropka Wojciech Czyszczoń Dmitry Ghilarov Stefan Grätz Jonathan G Heddle Bernhard Loll Roderich D Süssmuth Marcus Fulde |
| author_facet | Mareike Saathoff Simone Kosol Torsten Semmler Karsten Tedin Nicole Dimos Johannes Kupke Maria Seidel Fereshteh Ghazisaeedi Micela Condor Jonske Silver A Wolf Benno Kuropka Wojciech Czyszczoń Dmitry Ghilarov Stefan Grätz Jonathan G Heddle Bernhard Loll Roderich D Süssmuth Marcus Fulde |
| author_sort | Mareike Saathoff |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-eeba2ab4be8d437b83a1dd0386ce840c |
| institution | DOAJ |
| issn | 1544-9173 1545-7885 |
| language | English |
| publishDate | 2023-08-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj-art-eeba2ab4be8d437b83a1dd0386ce840c2025-08-20T03:01:22ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852023-08-01218e300218610.1371/journal.pbio.3002186Gene amplifications cause high-level resistance against albicidin in gram-negative bacteria.Mareike SaathoffSimone KosolTorsten SemmlerKarsten TedinNicole DimosJohannes KupkeMaria SeidelFereshteh GhazisaeediMicela Condor JonskeSilver A WolfBenno KuropkaWojciech CzyszczońDmitry GhilarovStefan GrätzJonathan G HeddleBernhard LollRoderich D SüssmuthMarcus FuldeAntibiotic 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.https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3002186&type=printable |
| spellingShingle | Mareike Saathoff Simone Kosol Torsten Semmler Karsten Tedin Nicole Dimos Johannes Kupke Maria Seidel Fereshteh Ghazisaeedi Micela Condor Jonske Silver A Wolf Benno Kuropka Wojciech Czyszczoń Dmitry Ghilarov Stefan Grätz Jonathan G Heddle Bernhard Loll Roderich D Süssmuth Marcus Fulde Gene amplifications cause high-level resistance against albicidin in gram-negative bacteria. PLoS Biology |
| title | Gene amplifications cause high-level resistance against albicidin in gram-negative bacteria. |
| title_full | Gene amplifications cause high-level resistance against albicidin in gram-negative bacteria. |
| title_fullStr | Gene amplifications cause high-level resistance against albicidin in gram-negative bacteria. |
| title_full_unstemmed | Gene amplifications cause high-level resistance against albicidin in gram-negative bacteria. |
| title_short | Gene amplifications cause high-level resistance against albicidin in gram-negative bacteria. |
| title_sort | gene amplifications cause high level resistance against albicidin in gram negative bacteria |
| url | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3002186&type=printable |
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