Sristi Raj Rai, Amity University Kolkata
Handicapped microbes that survive drug attacks are more dangerous than the living ones, as very soon they develop resistance to that specific drug. Macrolides, a class of broad-spectrum antibiotics that has a macrocyclic structure are produced by strains of Streptomyces. These are generally prescribed in case of bacterial infections and include Zithromax (Azithromycin), Biaxin (Clarithromycin), Dificid (Fidoximycin), and Erythromycin. All of them inhibits bacterial growth & replication by binding to the ribosomal machinery (blocking the 50s subunit), thus perturbs protein biosynthesis (translation). But soon, these bacteria survived the battle against these drugs, and people started to suffer and die. Therefore, it was important to pinpoint the reason behind their power.
Maxim S. Svetlov et al. figured a way out how these bacteria might have been blocking this drug. It was found that the resistant species had their 70s ribosomes modified to prevent binding of the macrolides upon entering into their system. High-resolution images (2.4 Å resolutions) of the antibiotic-ribosome binding complex made it possible to take a deeper look into the mechanism. When the results from the resistant-type were compared to the sensitive-type, they observed a missing water molecule in the resistant ones. This water molecule is required for the perfect tight binding of antibiotics and acted as a bridge. But due to the modified ribosome structure, there was no space left for the molecule. Hence, the reason behind the failure of the drug action was revealed. This research will pave the way for the development of an improved and new drug that can act independently of the bridging water molecule.
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SOURCE – Svetlov, M.S., Syroegin, E.A., Aleksandrova, E.V. et al. Structure of Erm-modified 70S ribosome reveals the mechanism of macrolide resistance. Nat Chem Biol (2021). https://doi.org/10.1038/s41589-020-00715-0
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