Exquisite selectivity of griselimycin extends to beta subunit of DNA polymerases from Gram-negative bacterial pathogens

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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Main Authors: 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
Format: Article
Language:English
Published: Nature Portfolio 2024-12-01
Series:Communications Biology
Online Access:https://doi.org/10.1038/s42003-024-07175-5
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Summary: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.
ISSN:2399-3642

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