The discovery and structural basis of two distinct state-dependent inhibitors of BamA

Dawei Sun, Kelly M. Storek, Dimitry Tegunov, Ying Yang, Christopher P. Arthur, Matthew Johnson, John G. Quinn, Weijing Liu, Guanghui Han, Hany S. Girgis, Mary Kate Alexander, Austin K. Murchison, Stephanie Shriver, Christine Tam, Hiroshi Ijiri, Hiroko Inaba, Tatsuya Sano, Hayato Yanagida, Junichi Nishikawa, Christopher E. Heise, Wayne J. Fairbrother, Man-Wah Tan, Nicholas Skelton, Wendy Sandoval, Benjamin D. Sellers, Claudio Ciferri, Peter A. Smith, Patrick C. Reid, Christian N. Cunningham (), Steven T. Rutherford () and Jian Payandeh ()
Additional contact information
Dawei Sun: Genentech Inc.
Kelly M. Storek: Genentech Inc.
Dimitry Tegunov: Genentech Inc.
Ying Yang: Genentech Inc.
Christopher P. Arthur: Genentech Inc.
Matthew Johnson: Genentech Inc.
John G. Quinn: Genentech Inc.
Weijing Liu: Genentech Inc.
Guanghui Han: Genentech Inc.
Hany S. Girgis: Genentech Inc.
Mary Kate Alexander: Genentech Inc.
Austin K. Murchison: Genentech Inc.
Stephanie Shriver: Genentech Inc.
Christine Tam: Genentech Inc.
Hiroshi Ijiri: PeptiDream Inc.
Hiroko Inaba: PeptiDream Inc.
Tatsuya Sano: PeptiDream Inc.
Hayato Yanagida: PeptiDream Inc.
Junichi Nishikawa: PeptiDream Inc.
Christopher E. Heise: Genentech Inc.
Wayne J. Fairbrother: Genentech Inc.
Man-Wah Tan: Genentech Inc.
Nicholas Skelton: Genentech Inc.
Wendy Sandoval: Genentech Inc.
Benjamin D. Sellers: Genentech Inc.
Claudio Ciferri: Genentech Inc.
Peter A. Smith: Genentech Inc.
Patrick C. Reid: PeptiDream Inc.
Christian N. Cunningham: Genentech Inc.
Steven T. Rutherford: Genentech Inc.
Jian Payandeh: Genentech Inc.

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract BamA is the central component of the essential β-barrel assembly machine (BAM), a conserved multi-subunit complex that dynamically inserts and folds β-barrel proteins into the outer membrane of Gram-negative bacteria. Despite recent advances in our mechanistic and structural understanding of BamA, there are few potent and selective tool molecules that can bind to and modulate BamA activity. Here, we explored in vitro selection methods and different BamA/BAM protein formulations to discover peptide macrocycles that kill Escherichia coli by targeting extreme conformational states of BamA. Our studies show that Peptide Targeting BamA-1 (PTB1) targets an extracellular divalent cation-dependent binding site and locks BamA into a closed lateral gate conformation. By contrast, PTB2 targets a luminal binding site and traps BamA into an open lateral gate conformation. Our results will inform future antibiotic discovery efforts targeting BamA and provide a template to prospectively discover modulators of other dynamic integral membrane proteins.

Date: 2024
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DOI: 10.1038/s41467-024-52512-1

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