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  1. Article ; Online: Exotoxin-Targeted Drug Modalities as Antibiotic Alternatives.

    Sakari, Moona / Laisi, Arttu / Pulliainen, Arto T

    ACS infectious diseases

    2022  Volume 8, Issue 3, Page(s) 433–456

    Abstract: The paradigm of antivirulence therapy dictates that bacterial pathogens are specifically disarmed but not killed by neutralizing their virulence factors. Clearance of the invading pathogen by the immune system is promoted. As compared to antibiotics, the ...

    Abstract The paradigm of antivirulence therapy dictates that bacterial pathogens are specifically disarmed but not killed by neutralizing their virulence factors. Clearance of the invading pathogen by the immune system is promoted. As compared to antibiotics, the pathogen-selective antivirulence drugs hold promise to minimize collateral damage to the beneficial microbiome. Also, selective pressure for resistance is expected to be lower because bacterial viability is not directly affected. Antivirulence drugs are being developed for stand-alone prophylactic and therapeutic treatments but also for combinatorial use with antibiotics. This Review focuses on drug modalities that target bacterial exotoxins after the secretion or release-upon-lysis. Exotoxins have a significant and sometimes the primary role as the disease-causing virulence factor, and thereby they are attractive targets for drug development. We describe the key pre-clinical and clinical trial data that have led to the approval of currently used exotoxin-targeted drugs, namely the monoclonal antibodies bezlotoxumab (toxin B/TcdB,
    MeSH term(s) Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/therapeutic use ; Bacillus anthracis ; Bacterial Toxins ; Clostridioides difficile ; Exotoxins
    Chemical Substances Anti-Bacterial Agents ; Bacterial Toxins ; Exotoxins
    Language English
    Publishing date 2022-01-31
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ISSN 2373-8227
    ISSN (online) 2373-8227
    DOI 10.1021/acsinfecdis.1c00296
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Crystal structures of pertussis toxin with NAD

    Sakari, Moona / Tran, Mai T / Rossjohn, Jamie / Pulliainen, Arto T / Beddoe, Travis / Littler, Dene R

    The Journal of biological chemistry

    2022  Volume 298, Issue 5, Page(s) 101892

    Abstract: Bordetella pertussis is the causative agent of whooping cough, a highly contagious respiratory disease. Pertussis toxin (PT), a major virulence factor secreted by B. pertussis, is an AB5-type protein complex topologically related to cholera toxin. The PT ...

    Abstract Bordetella pertussis is the causative agent of whooping cough, a highly contagious respiratory disease. Pertussis toxin (PT), a major virulence factor secreted by B. pertussis, is an AB5-type protein complex topologically related to cholera toxin. The PT protein complex is internalized by host cells and follows a retrograde trafficking route to the endoplasmic reticulum, where it subsequently dissociates. The released enzymatic S1 subunit is then translocated from the endoplasmic reticulum into the cytosol and subsequently ADP-ribosylates the inhibitory alpha-subunits (Gαi) of heterotrimeric G proteins, thus promoting dysregulation of G protein-coupled receptor signaling. However, the mechanistic details of the ADP-ribosylation activity of PT are not well understood. Here, we describe crystal structures of the S1 subunit in complex with nicotinamide adenine dinucleotide (NAD+), with NAD+ hydrolysis products ADP-ribose and nicotinamide, with NAD+ analog PJ34, and with a novel NAD+ analog formed upon S1 subunit crystallization with 3-amino benzamide and NAD+, which we name benzamide amino adenine dinucleotide. These crystal structures provide unprecedented insights into pre- and post-NAD+ hydrolysis steps of the ADP-ribosyltransferase activity of PT. We propose that these data may aid in rational drug design approaches and further development of PT-specific small-molecule inhibitors.
    MeSH term(s) ADP-Ribosylation ; Adenosine Diphosphate Ribose/metabolism ; Bordetella pertussis ; Cytosol/metabolism ; NAD/metabolism ; Pertussis Toxin/chemistry ; Virulence Factors, Bordetella/chemistry
    Chemical Substances Virulence Factors, Bordetella ; NAD (0U46U6E8UK) ; Adenosine Diphosphate Ribose (20762-30-5) ; Pertussis Toxin (EC 2.4.2.31)
    Language English
    Publishing date 2022-04-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2022.101892
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo.

    Ernst, Katharina / Mittler, Ann-Katrin / Winkelmann, Veronika / Kling, Carolin / Eberhardt, Nina / Anastasia, Anna / Sonnabend, Michael / Lochbaum, Robin / Wirsching, Jan / Sakari, Moona / Pulliainen, Arto T / Skerry, Ciaran / Carbonetti, Nicholas H / Frick, Manfred / Barth, Holger

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 5429

    Abstract: Whooping cough is caused by Bordetella pertussis that releases pertussis toxin (PT) which comprises enzyme A-subunit PTS1 and binding/transport B-subunit. After receptor-mediated endocytosis, PT reaches the endoplasmic reticulum from where unfolded PTS1 ... ...

    Abstract Whooping cough is caused by Bordetella pertussis that releases pertussis toxin (PT) which comprises enzyme A-subunit PTS1 and binding/transport B-subunit. After receptor-mediated endocytosis, PT reaches the endoplasmic reticulum from where unfolded PTS1 is transported to the cytosol. PTS1 ADP-ribosylates G-protein α-subunits resulting in increased cAMP signaling. Here, a role of target cell chaperones Hsp90, Hsp70, cyclophilins and FK506-binding proteins for cytosolic PTS1-uptake is demonstrated. PTS1 specifically and directly interacts with chaperones in vitro and in cells. Specific pharmacological chaperone inhibition protects CHO-K1, human primary airway basal cells and a fully differentiated airway epithelium from PT-intoxication by reducing intracellular PTS1-amounts without affecting cell binding or enzyme activity. PT is internalized by human airway epithelium secretory but not ciliated cells and leads to increase of apical surface liquid. Cyclophilin-inhibitors reduced leukocytosis in infant mouse model of pertussis, indicating their promising potential for developing novel therapeutic strategies against whooping cough.
    MeSH term(s) Animals ; Bordetella pertussis/enzymology ; Bordetella pertussis/metabolism ; Bordetella pertussis/pathogenicity ; CHO Cells ; Cricetulus ; Drug Delivery Systems ; Enzyme Inhibitors/pharmacology ; Epithelial Cells/metabolism ; Epithelial Cells/microbiology ; HEK293 Cells ; Humans ; Leukocytosis/chemically induced ; Leukocytosis/drug therapy ; Leukocytosis/metabolism ; Mice ; Molecular Chaperones/antagonists & inhibitors ; Molecular Chaperones/genetics ; Molecular Chaperones/metabolism ; Pertussis Toxin/toxicity
    Chemical Substances Enzyme Inhibitors ; Molecular Chaperones ; Pertussis Toxin (EC 2.4.2.31)
    Language English
    Publishing date 2021-03-08
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-84817-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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