The bacteriophage LUZ24 “Igy” peptide inhibits the Pseudomonas DNA gyrase

• Published in: Cell reports (Cambridge) 2021-08, Vol.36 (8), p.109567-109567, Article 109567
• Main Authors: De Smet, Jeroen, Wagemans, Jeroen, Boon, Maarten, Ceyssens, Pieter-Jan, Voet, Marleen, Noben, Jean-Paul, Andreeva, Julia, Ghilarov, Dmitry, Severinov, Konstantin, Lavigne, Rob
• Format: Article
• Language: English
• Subjects: bacteriophage; DNA gyrase; DNA Gyrase - genetics; DNA Gyrase - metabolism; DNA Replication; DNA, Bacterial - biosynthesis; DNA, Bacterial - genetics; drug discovery; ORFan; Podoviridae - genetics; Podoviridae - metabolism; Pseudomonas aeruginosa; Pseudomonas aeruginosa - genetics; Pseudomonas aeruginosa - metabolism; Pseudomonas aeruginosa - virology; Pseudomonas Phages - genetics; Pseudomonas Phages - metabolism; Topoisomerase II Inhibitors - metabolism; Viral Proteins - genetics; Viral Proteins - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109567

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. [Display omitted] •An early gene of phage LUZ24 inhibits the DNA gyrase subunit B of P. aeruginosa•This gene is therefore coined Igy, inhibitor of gyrase•Igy most likely interferes with the gyrase’s ability to bind DNA by using DNA mimicry•Igy holds potential for the development of antibiotics De Smet et al. explore one of the orphan early genes of a bacteriophage infecting Pseudomonas aeruginosa. They reveal its activity as a gyrase inhibitor, with potential for drug development. As such, they offer an additional example of how this viral dark matter could be mined for biotechnological applications.