The bacteriophage LUZ24 “Igy” peptide inhibits the Pseudomonas DNA gyrase
Jeroen De Smet,
Jeroen Wagemans,
Maarten Boon,
Pieter-Jan Ceyssens,
Marleen Voet,
Jean-Paul Noben,
Julia Andreeva,
Dmitry Ghilarov,
Konstantin Severinov,
Rob Lavigne
Affiliations
Jeroen De Smet
Laboratory of Gene Technology, Department of Biosystems, KU Leuven, 3001 Leuven, Belgium
Jeroen Wagemans
Laboratory of Gene Technology, Department of Biosystems, KU Leuven, 3001 Leuven, Belgium
Maarten Boon
Laboratory of Gene Technology, Department of Biosystems, KU Leuven, 3001 Leuven, Belgium
Pieter-Jan Ceyssens
Laboratory of Gene Technology, Department of Biosystems, KU Leuven, 3001 Leuven, Belgium
Marleen Voet
Laboratory of Gene Technology, Department of Biosystems, KU Leuven, 3001 Leuven, Belgium
Jean-Paul Noben
Biomedical Research Institute and Transnational University Limburg, School of Life Sciences, Hasselt University, 3590 Diepenbeek, Belgium
Julia Andreeva
Centre for Life Sciences, Skolkovo Institute of Science and Technology, 143026 Moscow, Russia
Dmitry Ghilarov
Centre for Life Sciences, Skolkovo Institute of Science and Technology, 143026 Moscow, Russia
Konstantin Severinov
Centre for Life Sciences, Skolkovo Institute of Science and Technology, 143026 Moscow, Russia; Waksman Institute for Microbiology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
Rob Lavigne
Laboratory of Gene Technology, Department of Biosystems, KU Leuven, 3001 Leuven, Belgium; Corresponding author
Summary: The bacterial DNA gyrase complex (GyrA/GyrB) plays a crucial role during DNA replication and serves as a target for multiple antibiotics, including the fluoroquinolones. Despite it being a valuable antibiotics target, resistance emergence by pathogens including Pseudomonas aeruginosa are proving problematic. Here, we describe Igy, a peptide inhibitor of gyrase, encoded by Pseudomonas bacteriophage LUZ24 and other members of the Bruynoghevirus genus. Igy (5.6 kDa) inhibits in vitro gyrase activity and interacts with the P. aeruginosa GyrB subunit, possibly by DNA mimicry, as indicated by a de novo model of the peptide and mutagenesis. In vivo, overproduction of Igy blocks DNA replication and leads to cell death also in fluoroquinolone-resistant bacterial isolates. These data highlight the potential of discovering phage-inspired leads for antibiotics development, supported by co-evolution, as Igy may serve as a scaffold for small molecule mimicry to target the DNA gyrase complex, without cross-resistance to existing molecules.
