Exquisite selectivity of griselimycin extends to beta subunit of DNA polymerases from Gram-negative bacterial pathogens PMID: 39639052

ADC Targets in Oncology

2026-04-10

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

Commun Biol. 2024 Dec 5;7(1):1622. doi: 10.1038/s42003-024-07175-5.

Michael K Fenwick ^# ¹ ² , Phillip G Pierce ^# ¹ ³ , Jan Abendroth ¹ ³ , Kayleigh F Barrett ¹ ⁴ , Lynn K Barrett ¹ ⁴ , Kalinga Bowatte ¹ ³ , Ryan Choi ¹ ⁴ , Ian Chun ¹ ⁴ , Deborah G Conrady ¹ ³ , Justin K Craig ¹ ⁴ , David M Dranow ¹ ³ , Bradley Hammerson ¹ ² , Tate Higgins ¹ ³ , Donald D Lorimer ¹ ³ , Peer Lukat ⁵ , Stephen J Mayclin ¹ ³ , Stephen Nakazawa Hewitt ¹ ⁴ , Ying Po Peng ¹ ² , Ashwini Shanbhogue ¹ ⁴ , Hayden Smutney ¹ ³ , Matthew Z Z Stigliano ¹ ³ , Logan M Tillery ¹ ⁴ , Hannah S Udell ¹ , Ellen G Wallace ¹ ³ , Amy E DeRocher ¹ ² , Isabelle Q Phan ¹ ² , Bart L Staker ¹ ² , Sandhya Subramanian ¹ ² , Wesley C Van Voorhis ¹ ⁴ , Wulf Blankenfeldt ⁵ ⁶ , Rolf Müller ⁷ ⁸ ⁹ , Thomas E Edwards ¹⁰ ¹¹ ¹² ¹³ , Peter J Myler ¹⁴ ¹⁵ ¹⁶ ¹⁷ ¹⁸

Affiliations

1. Seattle Structural Genomics Center for Infectious Disease, 307 Westlake Avenue North, Seattle, WA, 98109, USA.
2. Center for Global Infectious Disease Research, Seattle Children's Research Institute, 307 Westlake Avenue North, Seattle, WA, 98109, USA.
3. UCB Biosciences, 7869 North East Day Road West, Bainbridge Island, WA, 98110, USA.
4. Department of Medicine, Division of Allergy and Infectious Diseases, Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, 1410 North East Campus Parkway, Seattle, WA, 98195, USA.
5. Structure and Function of Proteins, Helmholtz Center for Infection Research, Inhoffenstraße 7, 38124, Braunschweig, Germany.
6. Institute of Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, Spielmannstr. 7, 38106, Braunschweig, Germany.
7. Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), 66123, Saarbrücken, Germany. [email protected].
8. Department of Pharmacy, Saarland University, 66123, Saarbrücken, Germany. [email protected].
9. German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Inhoffenstraße 7, 38124, Braunschweig, Germany. [email protected].
10. Seattle Structural Genomics Center for Infectious Disease, 307 Westlake Avenue North, Seattle, WA, 98109, USA. [email protected].
11. UCB Biosciences, 7869 North East Day Road West, Bainbridge Island, WA, 98110, USA. [email protected].
12. Department of Global Health, University of Washington, 1410 North East Campus Parkway, Seattle, WA, 98195, USA. [email protected].
13. Department of Pediatrics, University of Washington, 1410 North East Campus Parkway, Seattle, WA, 98195, USA. [email protected].
14. Seattle Structural Genomics Center for Infectious Disease, 307 Westlake Avenue North, Seattle, WA, 98109, USA. [email protected].
15. Center for Global Infectious Disease Research, Seattle Children's Research Institute, 307 Westlake Avenue North, Seattle, WA, 98109, USA. [email protected].
16. Department of Global Health, University of Washington, 1410 North East Campus Parkway, Seattle, WA, 98195, USA. [email protected].
17. Department of Pediatrics, University of Washington, 1410 North East Campus Parkway, Seattle, WA, 98195, USA. [email protected].
18. Department of Biomedical Informatics and Medical Education, University of Washington, 1410 North East Campus Parkway, Seattle, WA, 98195, USA. [email protected].
# Contributed equally.

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.