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

Sacco, Michael D.; Wang, Shaohui; Adapa, Swamy R.; Zhang, Xiujun; Lewandowski, Eric M.; Gongora, Maura V.; Keramisanou, Dimitra; Atlas, Zachary D.; Townsend, Julia A.; Gatdula, Jean R.; Morgan, Ryan T.; Hammond, Lauren R.; Marty, Michael T.; Wang, Jun; Eswara, Prahathees J.; Gelis, Ioannis; Jiang, Rays H. Y.; Sun, Xingmin; Chen, Yu

doi:10.1038/s41467-022-32086-6

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

Abstract

AbstractTreatment 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 inmore » adverse or anaerobic environments.« less

Authors:

Sacco, Michael D. ^[1]; Wang, Shaohui ^[1]; Adapa, Swamy R. ^[2]; Zhang, Xiujun ^[1]; Lewandowski, Eric M. ^[1];

^[1]; Keramisanou, Dimitra ^[1]; Atlas, Zachary D. ^[1]; Townsend, Julia A. ^[3]; Gatdula, Jean R. ^[1];

^[1]; Hammond, Lauren R. ^[1];

^[3];

^[4];

^[1]; Gelis, Ioannis ^[1]; Jiang, Rays H. Y. ^[2]; Sun, Xingmin ^[1];

^[1]

Univ. of South Florida, Tampa, FL (United States)
Univ. of South Florida, Tampa, FL (United States). College of Public Health
Univ. of Arizona, Tucson, AZ (United States)
Rutgers Univ., Piscataway, NJ (United States)

Publication Date:: Thu Jul 28 00:00:00 EDT 2022

Research Org.:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Org.:: USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH)

OSTI Identifier:: 1879695

Alternate Identifier(s):: OSTI ID: 1900634

Grant/Contract Number:: AC02-06CH11357; S10_RR25528; S10_RR028976; R21 AI147654; R01 AI161762; R01 AI132711; R35 GM128624; R35 GM133617; T32 GM008804

Resource Type:: Accepted Manuscript

Journal Name:: Nature Communications

Additional Journal Information:: Journal Volume: 13; Journal Issue: 1; Journal ID: ISSN 2041-1723

Publisher:: Nature Publishing Group

Country of Publication:: United States

Language:: ENGLISH

Subject:: 59 BASIC BIOLOGICAL SCIENCES; antimicrobial resistance; bacteriology; pathogens; x-ray crystallography

Citation Formats


                    Sacco, Michael D., Wang, Shaohui, Adapa, Swamy R., Zhang, Xiujun, Lewandowski, Eric M., Gongora, Maura V., Keramisanou, Dimitra, Atlas, Zachary D., Townsend, Julia A., Gatdula, Jean R., Morgan, Ryan T., Hammond, Lauren R., Marty, Michael T., Wang, Jun, Eswara, Prahathees J., Gelis, Ioannis, Jiang, Rays H. Y., Sun, Xingmin, and Chen, Yu. A unique class of Zn2+-binding serine-based PBPs underlies cephalosporin resistance and sporogenesis in Clostridioides difficile.  United States: N. p., 2022. 
Web.  doi:10.1038/s41467-022-32086-6.

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                    Sacco, Michael D., Wang, Shaohui, Adapa, Swamy R., Zhang, Xiujun, Lewandowski, Eric M., Gongora, Maura V., Keramisanou, Dimitra, Atlas, Zachary D., Townsend, Julia A., Gatdula, Jean R., Morgan, Ryan T., Hammond, Lauren R., Marty, Michael T., Wang, Jun, Eswara, Prahathees J., Gelis, Ioannis, Jiang, Rays H. Y., Sun, Xingmin, & Chen, Yu. A unique class of Zn2+-binding serine-based PBPs underlies cephalosporin resistance and sporogenesis in Clostridioides difficile.  United States.  https://doi.org/10.1038/s41467-022-32086-6

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                    Sacco, Michael D., Wang, Shaohui, Adapa, Swamy R., Zhang, Xiujun, Lewandowski, Eric M., Gongora, Maura V., Keramisanou, Dimitra, Atlas, Zachary D., Townsend, Julia A., Gatdula, Jean R., Morgan, Ryan T., Hammond, Lauren R., Marty, Michael T., Wang, Jun, Eswara, Prahathees J., Gelis, Ioannis, Jiang, Rays H. Y., Sun, Xingmin, and Chen, Yu. Thu .  
"A unique class of Zn2+-binding serine-based PBPs underlies cephalosporin resistance and sporogenesis in Clostridioides difficile".  United States.  https://doi.org/10.1038/s41467-022-32086-6.  https://www.osti.gov/servlets/purl/1879695.

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@article{osti_1879695,

  title        = {A unique class of Zn2+-binding serine-based PBPs underlies cephalosporin resistance and sporogenesis in Clostridioides difficile},

  author       = {Sacco, Michael D. and Wang, Shaohui and Adapa, Swamy R. and Zhang, Xiujun and Lewandowski, Eric M. and Gongora, Maura V. and Keramisanou, Dimitra and Atlas, Zachary D. and Townsend, Julia A. and Gatdula, Jean R. and Morgan, Ryan T. and Hammond, Lauren R. and Marty, Michael T. and Wang, Jun and Eswara, Prahathees J. and Gelis, Ioannis and Jiang, Rays H. Y. and Sun, Xingmin and Chen, Yu},

  abstractNote = {AbstractTreatment 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.},

  doi          = {10.1038/s41467-022-32086-6},

  journal      = {Nature Communications},

  number       = 1,

  volume       = 13,

  place        = {United States},

  year         = {Thu Jul 28 00:00:00 EDT 2022},

  month        = {Thu Jul 28 00:00:00 EDT 2022}

}

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Structure and conformational dynamics of Clostridioides difficile toxin A

Journal Article Chen, Baohua ; Basak, Sujit ; Chen, Peng ; ... - Life Science Alliance

Clostridioides difficile toxin A and B (TcdA and TcdB) are two major virulence factors responsible for diseases associated with C. difficile infection (CDI). Here, we report the 3.18-Å resolution crystal structure of a TcdA fragment (residues L843–T2481), which advances our understanding of the complete structure of TcdA holotoxin. Our structural analysis, together with complementary single molecule FRET and limited proteolysis studies, reveal that TcdA adopts a dynamic structure and its CROPs domain can sample a spectrum of open and closed conformations in a pH-dependent manner. Furthermore, a small globular subdomain (SGS) and the CROPs protect the pore-forming region of TcdAmore »« less
https://doi.org/10.26508/lsa.202201383

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

Overview of the CCP 4 suite and current developments
journal, March 2011

Glycosyltransferases and Transpeptidases/Penicillin-Binding Proteins: Valuable Targets for New Antibacterials
journal, February 2016

Structural coordination of polymerization and crosslinking by a SEDS–bPBP peptidoglycan synthase complex
journal, March 2020

Rational design of a new antibiotic class for drug-resistant infections
journal, September 2021

Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis
journal, December 2013

Iterative model building, structure refinement and density modification with the PHENIX AutoBuild wizard
journal, December 2007

Structure of a Zn2+-containing D-alanyl-D-alanine-cleaving carboxypeptidase at 2.5 Å resolution
journal, September 1982

Comparative genome and phenotypic analysis of Clostridium difficile 027 strains provides insight into the evolution of a hypervirulent bacterium
journal, January 2009

Peptidoglycan Cross-Linking Activity of L,D-Transpeptidases from Clostridium difficile and Inactivation of These Enzymes by β-Lactams
journal, October 2017

ImageJ2: ImageJ for the next generation of scientific image data
journal, November 2017

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journal, May 2015

Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix
journal, October 2019

The penicillin-binding proteins: structure and role in peptidoglycan biosynthesis
journal, March 2008

Structural basis for effectiveness of siderophore-conjugated monocarbams against clinically relevant strains of Pseudomonas aeruginosa
journal, December 2010

How good are my data and what is the resolution?
journal, June 2013

How allosteric control of Staphylococcus aureus penicillin binding protein 2a enables methicillin resistance and physiological function
journal, October 2013

The Immune Protein Calprotectin Impacts Clostridioides difficile Metabolism through Zinc Limitation
journal, December 2019

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journal, February 2018

Interactions of zinc- and redox-signaling pathways
journal, May 2021

Sequencing and functional analysis of the genome of Bacillus subtilis strain 168
journal, June 1996

MoRDa , an automatic molecular replacement pipeline
journal, August 2015

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journal, January 2020

Reversible inactivation of a peptidoglycan transpeptidase by a β-lactam antibiotic mediated by β-lactam-ring recyclization in the enzyme active site
journal, August 2017

Clostridium difficile Has an Original Peptidoglycan Structure with a High Level of N-Acetylglucosamine Deacetylation and Mainly 3-3 Cross-links
journal, August 2011

Clostridium difficile Infection
journal, April 2015

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journal, September 2016

iMOSFLM : a new graphical interface for diffraction-image processing with MOSFLM
journal, March 2011

Metallo‐β‐Lactamases: A Class Apart
journal, August 1998

SEDS proteins are a widespread family of bacterial cell wall polymerases
journal, August 2016

Heliobacterium modesticaldum, sp. nov., a thermophilic heliobacterium of hot springs and volcanic soils
journal, April 1995

Determination of the in vitro Sporulation Frequency of Clostridium difficile
journal, January 2017

The PSIPRED protein structure prediction server
journal, April 2000

Zinc finger proteins: new insights into structural and functional diversity
journal, February 2001

Bis‐Cyclic Guanidines as a Novel Class of Compounds Potent against Clostridium difficile
journal, June 2018

Elimination of a good leaving group from the 3'-position of a cephalosporin need not be concerted with .beta.-lactam ring opening: TEM-2 .beta.-lactamase-catalyzed hydrolysis of pyridine-2-azo-4'-(N',N'-dimethylaniline) cephalosporin (PADAC) and of cephaloridine
journal, March 1984

Coot model-building tools for molecular graphics
journal, November 2004

REFMAC 5 for the refinement of macromolecular crystal structures
journal, March 2011

Crystal Structure of Penicillin-Binding Protein 3 (PBP3) from Escherichia coli
journal, May 2014

Penicillin-binding protein SpoVD disulphide is a target for StoA in Bacillus subtilis forespores
journal, January 2010

Molecular architecture of the PBP2–MreC core bacterial cell wall synthesis complex
journal, October 2017

Strain-Dependent RstA Regulation of Clostridioides difficile Toxin Production and Sporulation
journal, January 2020

Role of the Intestinal Microbiota in Resistance to Colonization by Clostridium difficile
journal, May 2014

Historical Perspectives on Studies of Clostridium difficile and C. difficile Infection
journal, January 2008

Automatic generation of protein structure cartoons with Pro-origami
journal, October 2011

Overview of Zinc Absorption and Excretion in the Human Gastrointestinal Tract
journal, May 2000

Cephamycins inhibit pathogen sporulation and effectively treat recurrent Clostridioides difficile infection
journal, August 2019

Metal and Redox Modulation of Cysteine Protein Function
journal, August 2003

HMMER web server: interactive sequence similarity searching
journal, May 2011

Penicillin Binding Proteins: key players in bacterial cell cycle and drug resistance processes
journal, September 2006

When anaerobes encounter oxygen: mechanisms of oxygen toxicity, tolerance and defence
journal, June 2021

A novel regulator controls C lostridium difficile sporulation, motility and toxin production: A novel regulator of C. difficile physiology
journal, March 2016

Profile hidden Markov models
journal, October 1998

Antistaphylococcal Activity of Ceftobiprole, a New Broad-Spectrum Cephalosporin
journal, October 2005

The Role of Reactive Oxygen Species in Antibiotic-Mediated Killing of Bacteria
journal, June 2017

Discovery of SARS-CoV-2 Papain-like Protease Inhibitors through a Combination of High-Throughput Screening and a FlipGFP-Based Reporter Assay
journal, June 2021

Recent advances in the understanding of antibiotic resistance in Clostridium difficile infection
journal, December 2015

Structural Insight into the Transglycosylation Step of Bacterial Cell-Wall Biosynthesis
journal, March 2007

Bayesian Deconvolution of Mass and Ion Mobility Spectra: From Binary Interactions to Polydisperse Ensembles
journal, April 2015

Petroclostridium xylanilyticum gen. nov., sp. nov., a xylan-degrading bacterium isolated from an oilfield, and reclassification of clostridial cluster III members into four novel genera in a new Hungateiclostridiaceae fam. nov.
journal, October 2018