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

Antibiotic resistance is a continuously increasing concern for public health care. Understanding resistance mechanisms and their emergence is crucial for the development of new antibiotics and their effective use. Here, we report the discovery of a gene amplification-based mechanism that imparts an...

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Published inbioRxiv
Main Authors Saathoff, Mareike, Kosol, Simone, Semmler, Torsten, Wolf, Silver A, Dimos, Nicole, Kupke, Johannes, Seidel, Maria, Ghaziasaeedi, Fereshteh, Tedin, Karsten, Kuropka, Benno, Czyszczon, Wojciech, Ghilarov, Dmitry, Graetz, Stefan, Heddle, Jonathan G, Loll, Bernhard, Suessmuth, Roderich D, Fulde, Marcus
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 15.09.2022
Subjects
Antibiotic resistance
Antibiotics
Copy number
Crystallography
Gene amplification
Gram-negative bacteria
Health care
Phylogeny
Public health
X-ray crystallography
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Summary:Antibiotic resistance is a continuously increasing concern for public health care. Understanding resistance mechanisms and their emergence is crucial for the development of new antibiotics and their effective use. Here, we report the discovery of a gene amplification-based mechanism that imparts an up to 1000-fold increase in resistance levels against the antibiotic albicidin. We show that this mechanism protects Salmonella Typhimurium and Escherichia coli by increasing the copy number of the GyrI-like transcription regulator STM3175 (YgiV) which binds albicidin. X-ray crystallography and molecular docking studies reveal a conserved binding motif 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 convey resistance in pathogens such as Vibrio vulnificus and Pseudomonas aeruginosa. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2022.09.15.507240