Towards Catalytic Antibiotics: Redesign of Aminoglycosides To Catalytically Disable Bacterial Ribosomes

Abstract

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.

Ribosome‐targeting antibacterial agents: Advances, challenges, and opportunities

“…Besides, molecular dynamics simulation has been used as a powerful method in ribosomal antibiotic discovery. Copper–aminoglycoside complexes have the ability to catalyze the hydrolysis of rRNA, however, compared to parent aminoglycosides, no significant enhancement in the antibacterial activity of these complexes 126 . To obtain catalytic aminoglycoside drugs with enhanced antibacterial potency, Smolkin et al 126 designed and synthesized four compounds by modifying the structure of neomycin B.…”

“…Copper–aminoglycoside complexes have the ability to catalyze the hydrolysis of rRNA, however, compared to parent aminoglycosides, no significant enhancement in the antibacterial activity of these complexes 126 . To obtain catalytic aminoglycoside drugs with enhanced antibacterial potency, Smolkin et al 126 designed and synthesized four compounds by modifying the structure of neomycin B. Different diamine moieties were introduced, as potential catalytic warheads for the hydrolysis of the phosphodiester bond between G1491 and A1492 of 16S rRNA 126 …”

“…To obtain catalytic aminoglycoside drugs with enhanced antibacterial potency, Smolkin et al 126 designed and synthesized four compounds by modifying the structure of neomycin B. Different diamine moieties were introduced, as potential catalytic warheads for the hydrolysis of the phosphodiester bond between G1491 and A1492 of 16S rRNA 126 …”

“…The simulation area was the 16S rRNA decoding A‐site targeted by neomycin B (Figure 11B). By analyzing the interactions of the four compounds with G1491, A1492, and A1493, the reason for the lack of catalytic activity of these compounds was clarified, which provides the basis for the development of next‐generation of catalytic aminoglycoside antibiotics 126 …”

Translational control of antibiotic resistance

“…It would be expected that, as this modified neomycin binds the ribosome, the diamine would stimulate cleavage of the 16 S rRNA, permanently disabling the ribosome. Although initial results do not reveal rRNA cleavage, structural data indicate that two diamine modifications do induce a significant structural change in the phosphate backbone of the 16 S rRNA [81]. Though this change is not sufficient to stimulate rRNA cleavage, this result indicates that, through remodelling of the diamine modification, these warheads will be effective in disabling ribosomes.…”