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- Title
Gene amplifications cause high-level resistance against albicidin in gram-negative bacteria.
- Authors
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
- 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. Antibiotic resistance is a continuously increasing concern for public health care. This study shows that transient gene amplification identifies a conserved transcriptional regulator as a resistance determinant against the peptide antibiotic albicidin in Gram-negative bacteria.
- Subjects
GRAM-negative bacteria; GENE amplification; PEPTIDE antibiotics; VIBRIO vulnificus; SMALL molecules; PSEUDOMONAS aeruginosa; GRAM-positive bacteria
- Publication
PLoS Biology, 2023, Vol 21, Issue 9, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3002186