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

PLoS Biol. 2023 Aug 10;21(8):e3002186. doi: 10.1371/journal.pbio.3002186. eCollection 2023 Aug.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents* / pharmacology
  • Gene Amplification*
  • Gram-Negative Bacteria / genetics
  • Gram-Positive Bacteria / metabolism
  • Molecular Docking Simulation
  • Phylogeny


  • albicidin
  • Anti-Bacterial Agents

Grants and funding

This work was supported by the DFG (SU 239/18-1 to R.S.), the priority program SPP2225 (FU 1027/4-1 to M.F.), and the Collaborative Research Centers CRC1449, Project ID 431232613; project B5 (to M.F. and F.G.). J.K. is financed by a scholarship from the H. Wilhelm Schaumann foundation. M.F. received support by the Freie Universität Berlin within the Excellence Initiative of the German Research Foundation. JGH is funded by a National Science Centre (NCN, Poland) grant no. 2020/39/B/NZ1/02898 (OPUS 20). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.