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Jin X , Daher SS , Lee M , Buttaro B , Andrade RB
Ribosome-Templated Azide-Alkyne Cycloadditions Using Resistant Bacteria as Reaction Vessels: in Cellulo Click Chemistry
ACS Med Chem Lett. 2018 Sep 13;9(9) :907-911
PMID: 30258539    PMCID: PMC6142060   
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Abstract
In situ click chemistry has been a powerful method for fragment-based drug design since its discovery in 2002. Recently, we demonstrated that the bacterial ribosome can template the azide-alkyne cycloaddition reaction to expedite the discovery of novel antibiotics. We now report this process can be performed in an antibiotic-resistant bacterial cell. The corresponding triazole products formed in cellulo are potent antibiotics that inhibit bacterial growth; moreover, the potency of each cycloadduct can be visualized using the traditional MIC assay in a 96-well plate format. We characterized the in cellulo clicked products by independent chemical synthesis and LC-MS analysis, which showed that mass count percent increase was directly proportional to 1/MIC. In other words, potent compounds detected by MIC were formed in greater amounts. Control experiments unambiguously showed the ribosome was responsible for templating triazole formation. Significantly, our method (1) obviates the need to isolate bacterial ribosomes; (2) could be applied to different bacterial strains, which broadens the scope and facilitates the discovery of narrow-spectrum antibiotics; and (3) does not require the knowledge of mode-of-action and thus could uncover novel antibiotic targets. We believe this method could be expanded and implemented as a novel approach for antibiotic drug discovery.
Notes
Jin, Xiao Daher, Samer S Lee, Miseon Buttaro, Bettina Andrade, Rodrigo B Journal Article United States ACS Med Chem Lett. 2018 Aug 13;9(9):907-911. doi: 10.1021/acsmedchemlett.8b00248. eCollection 2018 Sep 13.