Séminaire du Prof Ruchi Anand

Ruchi Anand est professeure au Department of Chemistry, Indian Institute of Technology Bombay (Inde)

Résumé (anglais)

Antibiotic resistance is a global pandemic that has emerged as a silent killer.Bacteria have harnessed several mechanisms to evade the effect of antibiotics with drug target modification being a highly efficient strategy utilized by pathogenic systems to render themselves resistant to antibiotics. The ribosome owing to its integral role as the protein synthesis machinery of the cell is a prime target for several antibiotics. Here, we unravel the mechanism of post-transcriptional ribosomal methylation which renders the macrolide lincosamide and streptogramin B ((MLSB) class of antibiotics ineffective. The enzyme Erythromycin-resistance methyltransferases (Erms),[1] exclusively harboured by several multi-drug resistant (MDR) pathogens can site specifically methylate a ribosomal base (A2058, E.coli numbering) in the nascent peptide exit tunnel of the 50S ribosomal subunit which then renders the MDRs resistant to MLSB class of drugs. Interestingly, we show that Erm is an opportunistic enzyme that exclusively targets ribosomal precursors. Using Cryogenic Electron Microscopy (Cryo-EM) we have trapped the Erm-precursor complex and showed how in a complex environment, during ribosomal biogenesis, Erm can methylate its substrate selectively. Moreover, corroborating single molecule FRET measurements were performed to understand the dynamic nature of these interactions and decipher states that the enzyme charters to achieve catalysis. Our work dwells into the unique dual base flipping mechanism employed by Erms to achieve catalysis and its evolutionary implications in the design of these enzymes that induce resistance in pathogenic strains.[3] Furthermore, the findings help in the identification of allosteric sites distal from the catalytic site of Erm which can serve as druggable targets. Subsequently, we have ongoing efforts towards AI-based drug design to specifically target Erm-based resistance thereby, facilitating ways of reversal of resistance. Overall, we draw a holistic picture of Erm’s action and delineate methods of curbing its pathogenic function.
Keywords: Antibiotic Resistance, MLSB, drug target modification, Erm methyltransferases, ribosomal precursors,
References:
1.    Singh et al., ACS Chem. Biol. 2022 Apr; 17(4):829-839.
2.    Bhujbalrao R, and Anand R, J. Am. Chem. Soc. 2019 Jan; 141(4):1425-1429.
3.    Bhujbalrao R, et al., J. Biol. Chem. 2022 Aug; 298(8):102208.

A propos de la conférencière

Ruchi Anand a obtenu son doctorat en chimie et biologie chimique à l'université Cornell et a ensuite effectué son travail postdoctoral au Memorial Sloan Kettering Cancer Center et à l'université de Pennsylvanie. Elle a rejoint l'Indian Institute of Technology Bombay (IIT Bombay) en 2008 et occupe actuellement le poste de professeur titulaire de la chaire de l'institut et de chef du département de chimie. Ses recherches combinent la cristallographie aux rayons X, la microscopie électronique cryogénique et les outils biochimiques pour étudier les mécanismes moléculaires pertinents pour la santé humaine, en se concentrant sur la résistance aux antimicrobiens et le développement de biocapteurs. Elle fait actuellement partie du comité consultatif de rédaction d'ACS Sensors, du Journal of Physical Chemistry (A/B/C), du Journal of the American Chemical Society (JACS) et est rédactrice en chef adjointe d'ACS Biochemistry. Elle est membre de l'India Alliance DBT-Wellcome Trust Senior Fellow et a récemment reçu la Sun Pharma Science Research Fellowship pour ses travaux dans le domaine des sciences pharmaceutiques. Elle est également élue membre des trois académies nationales des sciences en Inde.