Exquisite selectivity of griselimycin extends to beta subunit of DNA polymerases from Gram-negative bacterial pathogens
Abstract Griselimycin, a cyclic depsidecapeptide produced by Streptomyces griseus, is a promising lead inhibitor of the sliding clamp component of bacterial DNA polymerases (β-subunit of Escherichia coli DNA pol III). It was previously shown to inhibit the Mycobacterium tuberculosis β-clamp with rem...
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2024-12-01
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| Online Access: | https://doi.org/10.1038/s42003-024-07175-5 |
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| author | Michael K. Fenwick Phillip G. Pierce Jan Abendroth Kayleigh F. Barrett Lynn K. Barrett Kalinga Bowatte Ryan Choi Ian Chun Deborah G. Conrady Justin K. Craig David M. Dranow Bradley Hammerson Tate Higgins Donald D. Lorimer Peer Lukat Stephen J. Mayclin Stephen Nakazawa Hewitt Ying Po Peng Ashwini Shanbhogue Hayden Smutney Matthew Z. Z. Stigliano Logan M. Tillery Hannah S. Udell Ellen G. Wallace Amy E. DeRocher Isabelle Q. Phan Bart L. Staker Sandhya Subramanian Wesley C. Van Voorhis Wulf Blankenfeldt Rolf Müller Thomas E. Edwards Peter J. Myler |
| author_facet | Michael K. Fenwick Phillip G. Pierce Jan Abendroth Kayleigh F. Barrett Lynn K. Barrett Kalinga Bowatte Ryan Choi Ian Chun Deborah G. Conrady Justin K. Craig David M. Dranow Bradley Hammerson Tate Higgins Donald D. Lorimer Peer Lukat Stephen J. Mayclin Stephen Nakazawa Hewitt Ying Po Peng Ashwini Shanbhogue Hayden Smutney Matthew Z. Z. Stigliano Logan M. Tillery Hannah S. Udell Ellen G. Wallace Amy E. DeRocher Isabelle Q. Phan Bart L. Staker Sandhya Subramanian Wesley C. Van Voorhis Wulf Blankenfeldt Rolf Müller Thomas E. Edwards Peter J. Myler |
| author_sort | Michael K. Fenwick |
| collection | DOAJ |
| description | Abstract Griselimycin, a cyclic depsidecapeptide produced by Streptomyces griseus, is a promising lead inhibitor of the sliding clamp component of bacterial DNA polymerases (β-subunit of Escherichia coli DNA pol III). It was previously shown to inhibit the Mycobacterium tuberculosis β-clamp with remarkably high affinity and selectivity – the peptide lacks any interaction with the human sliding clamp. Here, we used a structural genomics approach to address the prospect of broader-spectrum inhibition, in particular of β-clamps from Gram-negative bacterial targets. Fifteen crystal structures of β-clamp orthologs were solved, most from Gram-negative bacteria, including eight cocrystal structures with griselimycin. The ensemble of structures samples widely diverse β-clamp architectures and reveals unique protein-ligand interactions with varying degrees of complementarity. Although griselimycin clearly co-evolved with Gram-positive β-clamps, binding affinity measurements demonstrate that the high selectivity observed previously extends to the Gram-negative orthologs, with K D values ranging from 7 to 496 nM for the wild-type orthologs considered. The collective results should aid future structure-guided development of peptide antibiotics against β-clamp proteins of a wide variety of bacterial targets. |
| format | Article |
| id | doaj-art-1a656d43c6764dba945de1b0c7cfbe21 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
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| series | Communications Biology |
| spelling | doaj-art-1a656d43c6764dba945de1b0c7cfbe212024-12-08T12:41:20ZengNature PortfolioCommunications Biology2399-36422024-12-017111310.1038/s42003-024-07175-5Exquisite selectivity of griselimycin extends to beta subunit of DNA polymerases from Gram-negative bacterial pathogensMichael K. Fenwick0Phillip G. Pierce1Jan Abendroth2Kayleigh F. Barrett3Lynn K. Barrett4Kalinga Bowatte5Ryan Choi6Ian Chun7Deborah G. Conrady8Justin K. Craig9David M. Dranow10Bradley Hammerson11Tate Higgins12Donald D. Lorimer13Peer Lukat14Stephen J. Mayclin15Stephen Nakazawa Hewitt16Ying Po Peng17Ashwini Shanbhogue18Hayden Smutney19Matthew Z. Z. Stigliano20Logan M. Tillery21Hannah S. Udell22Ellen G. Wallace23Amy E. DeRocher24Isabelle Q. Phan25Bart L. Staker26Sandhya Subramanian27Wesley C. Van Voorhis28Wulf Blankenfeldt29Rolf Müller30Thomas E. Edwards31Peter J. Myler32Seattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseStructure and Function of Proteins, Helmholtz Center for Infection ResearchSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseStructure and Function of Proteins, Helmholtz Center for Infection ResearchDepartment of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)Seattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious DiseaseAbstract Griselimycin, a cyclic depsidecapeptide produced by Streptomyces griseus, is a promising lead inhibitor of the sliding clamp component of bacterial DNA polymerases (β-subunit of Escherichia coli DNA pol III). It was previously shown to inhibit the Mycobacterium tuberculosis β-clamp with remarkably high affinity and selectivity – the peptide lacks any interaction with the human sliding clamp. Here, we used a structural genomics approach to address the prospect of broader-spectrum inhibition, in particular of β-clamps from Gram-negative bacterial targets. Fifteen crystal structures of β-clamp orthologs were solved, most from Gram-negative bacteria, including eight cocrystal structures with griselimycin. The ensemble of structures samples widely diverse β-clamp architectures and reveals unique protein-ligand interactions with varying degrees of complementarity. Although griselimycin clearly co-evolved with Gram-positive β-clamps, binding affinity measurements demonstrate that the high selectivity observed previously extends to the Gram-negative orthologs, with K D values ranging from 7 to 496 nM for the wild-type orthologs considered. The collective results should aid future structure-guided development of peptide antibiotics against β-clamp proteins of a wide variety of bacterial targets.https://doi.org/10.1038/s42003-024-07175-5 |
| spellingShingle | Michael K. Fenwick Phillip G. Pierce Jan Abendroth Kayleigh F. Barrett Lynn K. Barrett Kalinga Bowatte Ryan Choi Ian Chun Deborah G. Conrady Justin K. Craig David M. Dranow Bradley Hammerson Tate Higgins Donald D. Lorimer Peer Lukat Stephen J. Mayclin Stephen Nakazawa Hewitt Ying Po Peng Ashwini Shanbhogue Hayden Smutney Matthew Z. Z. Stigliano Logan M. Tillery Hannah S. Udell Ellen G. Wallace Amy E. DeRocher Isabelle Q. Phan Bart L. Staker Sandhya Subramanian Wesley C. Van Voorhis Wulf Blankenfeldt Rolf Müller Thomas E. Edwards Peter J. Myler Exquisite selectivity of griselimycin extends to beta subunit of DNA polymerases from Gram-negative bacterial pathogens Communications Biology |
| title | Exquisite selectivity of griselimycin extends to beta subunit of DNA polymerases from Gram-negative bacterial pathogens |
| title_full | Exquisite selectivity of griselimycin extends to beta subunit of DNA polymerases from Gram-negative bacterial pathogens |
| title_fullStr | Exquisite selectivity of griselimycin extends to beta subunit of DNA polymerases from Gram-negative bacterial pathogens |
| title_full_unstemmed | Exquisite selectivity of griselimycin extends to beta subunit of DNA polymerases from Gram-negative bacterial pathogens |
| title_short | Exquisite selectivity of griselimycin extends to beta subunit of DNA polymerases from Gram-negative bacterial pathogens |
| title_sort | exquisite selectivity of griselimycin extends to beta subunit of dna polymerases from gram negative bacterial pathogens |
| url | https://doi.org/10.1038/s42003-024-07175-5 |
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