The bacteriophage LUZ24 “Igy” peptide inhibits the Pseudomonas DNA gyrase
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 pr...
| Main Authors: | , , , , , , , , , |
|---|---|
| פורמט: | Article |
| שפה: | English |
| יצא לאור: |
Elsevier
2021-08-01
|
| סדרה: | Cell Reports |
| נושאים: | |
| גישה מקוונת: | http://www.sciencedirect.com/science/article/pii/S2211124721010019 |
| _version_ | 1829507160084578304 |
|---|---|
| author | Jeroen De Smet Jeroen Wagemans Maarten Boon Pieter-Jan Ceyssens Marleen Voet Jean-Paul Noben Julia Andreeva Dmitry Ghilarov Konstantin Severinov Rob Lavigne |
| author_facet | Jeroen De Smet Jeroen Wagemans Maarten Boon Pieter-Jan Ceyssens Marleen Voet Jean-Paul Noben Julia Andreeva Dmitry Ghilarov Konstantin Severinov Rob Lavigne |
| author_sort | Jeroen De Smet |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-16T11:02:32Z |
| format | Article |
| id | doaj.art-daf11f2b61e945c7b8398e6544f55c20 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-16T11:02:32Z |
| publishDate | 2021-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-daf11f2b61e945c7b8398e6544f55c202022-12-21T22:33:57ZengElsevierCell Reports2211-12472021-08-01368109567The bacteriophage LUZ24 “Igy” peptide inhibits the Pseudomonas DNA gyraseJeroen De Smet0Jeroen Wagemans1Maarten Boon2Pieter-Jan Ceyssens3Marleen Voet4Jean-Paul Noben5Julia Andreeva6Dmitry Ghilarov7Konstantin Severinov8Rob Lavigne9Laboratory of Gene Technology, Department of Biosystems, KU Leuven, 3001 Leuven, BelgiumLaboratory of Gene Technology, Department of Biosystems, KU Leuven, 3001 Leuven, BelgiumLaboratory of Gene Technology, Department of Biosystems, KU Leuven, 3001 Leuven, BelgiumLaboratory of Gene Technology, Department of Biosystems, KU Leuven, 3001 Leuven, BelgiumLaboratory of Gene Technology, Department of Biosystems, KU Leuven, 3001 Leuven, BelgiumBiomedical Research Institute and Transnational University Limburg, School of Life Sciences, Hasselt University, 3590 Diepenbeek, BelgiumCentre for Life Sciences, Skolkovo Institute of Science and Technology, 143026 Moscow, RussiaCentre for Life Sciences, Skolkovo Institute of Science and Technology, 143026 Moscow, RussiaCentre 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, USALaboratory of Gene Technology, Department of Biosystems, KU Leuven, 3001 Leuven, Belgium; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124721010019DNA gyrasePseudomonas aeruginosaORFanbacteriophagedrug discovery |
| spellingShingle | Jeroen De Smet Jeroen Wagemans Maarten Boon Pieter-Jan Ceyssens Marleen Voet Jean-Paul Noben Julia Andreeva Dmitry Ghilarov Konstantin Severinov Rob Lavigne The bacteriophage LUZ24 “Igy” peptide inhibits the Pseudomonas DNA gyrase Cell Reports DNA gyrase Pseudomonas aeruginosa ORFan bacteriophage drug discovery |
| title | The bacteriophage LUZ24 “Igy” peptide inhibits the Pseudomonas DNA gyrase |
| title_full | The bacteriophage LUZ24 “Igy” peptide inhibits the Pseudomonas DNA gyrase |
| title_fullStr | The bacteriophage LUZ24 “Igy” peptide inhibits the Pseudomonas DNA gyrase |
| title_full_unstemmed | The bacteriophage LUZ24 “Igy” peptide inhibits the Pseudomonas DNA gyrase |
| title_short | The bacteriophage LUZ24 “Igy” peptide inhibits the Pseudomonas DNA gyrase |
| title_sort | bacteriophage luz24 igy peptide inhibits the pseudomonas dna gyrase |
| topic | DNA gyrase Pseudomonas aeruginosa ORFan bacteriophage drug discovery |
| url | http://www.sciencedirect.com/science/article/pii/S2211124721010019 |
| work_keys_str_mv | AT jeroendesmet thebacteriophageluz24igypeptideinhibitsthepseudomonasdnagyrase AT jeroenwagemans thebacteriophageluz24igypeptideinhibitsthepseudomonasdnagyrase AT maartenboon thebacteriophageluz24igypeptideinhibitsthepseudomonasdnagyrase AT pieterjanceyssens thebacteriophageluz24igypeptideinhibitsthepseudomonasdnagyrase AT marleenvoet thebacteriophageluz24igypeptideinhibitsthepseudomonasdnagyrase AT jeanpaulnoben thebacteriophageluz24igypeptideinhibitsthepseudomonasdnagyrase AT juliaandreeva thebacteriophageluz24igypeptideinhibitsthepseudomonasdnagyrase AT dmitryghilarov thebacteriophageluz24igypeptideinhibitsthepseudomonasdnagyrase AT konstantinseverinov thebacteriophageluz24igypeptideinhibitsthepseudomonasdnagyrase AT roblavigne thebacteriophageluz24igypeptideinhibitsthepseudomonasdnagyrase AT jeroendesmet bacteriophageluz24igypeptideinhibitsthepseudomonasdnagyrase AT jeroenwagemans bacteriophageluz24igypeptideinhibitsthepseudomonasdnagyrase AT maartenboon bacteriophageluz24igypeptideinhibitsthepseudomonasdnagyrase AT pieterjanceyssens bacteriophageluz24igypeptideinhibitsthepseudomonasdnagyrase AT marleenvoet bacteriophageluz24igypeptideinhibitsthepseudomonasdnagyrase AT jeanpaulnoben bacteriophageluz24igypeptideinhibitsthepseudomonasdnagyrase AT juliaandreeva bacteriophageluz24igypeptideinhibitsthepseudomonasdnagyrase AT dmitryghilarov bacteriophageluz24igypeptideinhibitsthepseudomonasdnagyrase AT konstantinseverinov bacteriophageluz24igypeptideinhibitsthepseudomonasdnagyrase AT roblavigne bacteriophageluz24igypeptideinhibitsthepseudomonasdnagyrase |