IIT Bombay, Mumbai
Ruchi Anand is a Professor at IIT Bombay, Mumbai, She has done her PhD from Cornell University, USA. Her research interests are protein crystallography and structural biology. Ruchi Anand was elected Fellow of IASc in 2022.
Session 2C: Inaugural Lectures by Fellows/Associates
Rajiva Raman, Varanasi
Deciphering the Mechanism of Ribosomal Methyltransferase-mediated Antibiotic Resistance
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, 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 mechanisms 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 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 and 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 resistance-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. A combination of Cryo-EM, biochemical, fluorescence andMD approaches on both theMtases 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 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.