A unique class of Zn2+-binding serine-based PBPs underlies cephalosporin resistance and sporogenesis in Clostridioides difficile

Michael D. Sacco, Shaohui Wang, Swamy R. Adapa, Xiujun Zhang, Eric M. Lewandowski, Maura V. Gongora, Dimitra Keramisanou, Zachary D. Atlas, Julia A. Townsend, Jean R. Gatdula, Ryan T. Morgan, Lauren R. Hammond, Michael T. Marty, Jun Wang, Prahathees J. Eswara, Ioannis Gelis, Rays H. Y. Jiang, Xingmin Sun () and Yu Chen ()
Additional contact information
Michael D. Sacco: University of South Florida
Shaohui Wang: University of South Florida
Swamy R. Adapa: University of South Florida
Xiujun Zhang: University of South Florida
Eric M. Lewandowski: University of South Florida
Maura V. Gongora: University of South Florida
Dimitra Keramisanou: University of South Florida
Zachary D. Atlas: University of South Florida
Julia A. Townsend: The University of Arizona
Jean R. Gatdula: University of South Florida
Ryan T. Morgan: University of South Florida
Lauren R. Hammond: University of South Florida
Michael T. Marty: The University of Arizona
Jun Wang: Rutgers, the State University of New Jersey
Prahathees J. Eswara: University of South Florida
Ioannis Gelis: University of South Florida
Rays H. Y. Jiang: University of South Florida
Xingmin Sun: University of South Florida
Yu Chen: University of South Florida

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Treatment with β-lactam antibiotics, particularly cephalosporins, is a major risk factor for Clostridioides difficile infection. These broad-spectrum antibiotics irreversibly inhibit penicillin-binding proteins (PBPs), which are serine-based enzymes that assemble the bacterial cell wall. However, C. difficile has four different PBPs (PBP1-3 and SpoVD) with various roles in growth and spore formation, and their specific links to β-lactam resistance in this pathogen are underexplored. Here, we show that PBP2 (known to be essential for vegetative growth) is the primary bactericidal target for β-lactams in C. difficile. PBP2 is insensitive to cephalosporin inhibition, and this appears to be the main basis for cephalosporin resistance in this organism. We determine crystal structures of C. difficile PBP2, alone and in complex with β-lactams, revealing unique features including ligand-induced conformational changes and an active site Zn2+-binding motif that influences β-lactam binding and protein stability. The Zn2+-binding motif is also present in C. difficile PBP3 and SpoVD (which are known to be essential for sporulation), as well as in other bacterial taxa including species living in extreme environments and the human gut. We speculate that this thiol-containing motif and its cognate Zn2+ might function as a redox sensor to regulate cell wall synthesis for survival in adverse or anaerobic environments.

Date: 2022
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DOI: 10.1038/s41467-022-32086-6

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