A2 Refereed review article in a scientific journal
Exotoxin-Targeted Drug Modalities as Antibiotic Alternatives
Authors: Sakari Moona, Laisi Arttu, Pulliainen Arto T.
Publisher: AMER CHEMICAL SOC
Publication year: 2022
Journal: ACS Infectious Diseases
Journal name in source: ACS INFECTIOUS DISEASES
Journal acronym: ACS INFECT DIS
Volume: 8
Issue: 3
First page : 433
Last page: 456
Number of pages: 24
ISSN: 2373-8227
DOI: https://doi.org/10.1021/acsinfecdis.1c00296
Web address : https://pubs.acs.org/doi/10.1021/acsinfecdis.1c00296
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/174963697
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, Clostridioides difficile), raxibacumab (anthrax toxin, Bacillus anthracis), and obiltoxaximab (anthrax toxin, Bacillus anthracis), but also to challenges with some of the promising leads. We also highlight the recent developments in pre-clinical research sector to develop exotoxin-targeted drug modalities, i.e., monoclonal antibodies, antibody fragments, antibody mimetics, receptor analogs, neutralizing scaffolds, dominant-negative mutants, and small molecules. We describe how these exotoxin-targeted drug modalities work with high-resolution structural knowledge and highlight their advantages and disadvantages as antibiotic alternatives.
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