Keynote, Zero hunger (SDG 2), Good Health and Well-being (SDG 3)
Ribosomal Methylation as a marker of antibiotic resistance
Ruchi Anand Department of Chemistry, Indian Institute of Technology Bombay, Mumbai, India 400076
Antibiotic resistance has become a silent epidemic that will result in more than 300 million deaths by 2050, if no appropriate action is taken. Repurposing of existing antibiotics and devising strategies to curb resistance is an uphill task and has become increasingly difficult. Towards addressing this grave problem here, we combat the problem of origin of resistance itself and focus on understanding the mechanisms by which pathogens become resistant to existing drugs. One of the prevalent mechanism by which resistance is conferred is by post translationally modifying the protein synthesis machinery, the ribosome. Several antibiotics such as erythromycin bind to the ribosome and kill the pathogens by selectively stalling their protein synthesis. Ribosomal modifying enzymes such as methyltransferases (Mtases) do not allow certain antibiotics to bind the ribosome by methylating select ribosomal bases thereby, cause a steric clash at the antibiotic binding site, thus result in evading their action leading to antibiotic resistance. Here, we decipher the mechanism of action and selective targeting of these resistant conferring Mtases. We have used two enzymes KsgA and Erm both enzymes methylating adenine bases at the N6 position of select bases on 50S and 30S respectively [1] . A combination of Cryo- EM, biochemical, fluorescence and MD approaches on both the Mtases as well as chimeric version of the enzymes revealed that apart from base flipping at the target site, that is crucial for methylation, base flipping at a distal allosteric site, within the Mtase [1,2] . is key in selective recognition of the target RNA. These studies serve as stepping-stone towards development of exclusive inhibitors that can aid in resisting resistance. Reference: 1. Bhujbalrao, R., Anand, R., J. Am. Chem. Soc. 2019, 141 (4), 1425-1429. 2. Singh J, Raina R, Kutti, V R, Anand R., ACS Chem.Biol. 2022, https://doi.org/10.1021/acschembio.1c00732
© The Author(s), 2023
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