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.

PMID: 39639052 DOI: 10.1038/s42003-024-07175-5

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-125576

Griselimycin

98.3%, Bacterial Inhibitor

Bacterial

Infection

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