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Towards Catalytic Antibiotics: Redesign of Aminoglycosides To Catalytically Disable Bacterial Ribosomes
Author(s) -
Smolkin Boris,
Khoov Alina,
Pieńko Tomasz,
Shavit Michal,
Belakhov Valery,
Trylska Joanna,
Baasov Timor
Publication year - 2019
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201800549
Subject(s) - antibiotics , pseudomonas aeruginosa , ribosome , rational design , aminoglycoside , neomycin , bacteria , biology , antibacterial activity , microbiology and biotechnology , kanamycin , chemistry , biochemistry , genetics , rna , gene
The emergence of multidrug‐resistant pathogens that are resistant to the majority of currently available antibiotics is a significant clinical problem. The development of new antibacterial agents and novel approaches is therefore extremely important. We set out to explore the potential of catalytic antibiotics as a new paradigm in antibiotics research. Herein, we describe our pilot study on the design, synthesis, and biological testing of a series of new derivatives of the natural aminoglycoside antibiotic neomycin B for their potential action as catalytic antibiotics. The new derivatives showed significant antibacterial activity against wild‐type bacteria and were especially potent against resistant and pathogenic strains including Pseudomonas aeruginosa and methicillin‐resistant Staphylococcus aureus . Selected compounds displayed RNase activity even though the activity was not as high and specific as we would have expected. On the basis of the observed chemical and biochemical data, along with the comparative molecular dynamics simulations of the prokaryotic rRNA decoding site, we postulate that the rational design of catalytic antibiotics should involve not only their structure but also a comprehensive analysis of the rRNA A‐site dynamics.