Title : Strategies to Combat Antibiotic Resistance.
Speaker : Prof. Ruchi Anand, IIT Bombay.
Date : 12/01/2022, 05:30 PM , Online Mode.
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 why do pathogens become resistant to existing drugs. The problem pertaining to origins of antibiotic resistance involves unearthing molecular mechanisms that promote it. One way by which the bacteria become resistant is by effluxing the antibiotics out of cell using efflux pumps like tetracycline efflux pump. These pumps open and close via regulators that activate efflux and deplete antibiotic concentrations in the cells, we are trying to understand mechanisms pertaining to it [1,2].
Another mechanism by which resistance is conferred is by modifying the protein synthesis machinery, the ribosome. Several antibiotics bind to the ribosome and kill the pathogens by selectively stalling their protein synthesis. Ribosomal modifying enzymes such as methyltransferases do not allow certain antibiotics to bind the ribosome by cause a steric clash at the antibiotic binding site, thus result in evading their action leading to antibiotic resistance. Here, we aim to understand how the mechanism of action and selective targeting of these resistant conferring methyltransferases. We have used two enzymes KsgA and Erm methyltransferase to unravel the mechanism using a structure guided approach . By understanding the mechanism of targeting one can design exclusive inhibitors that can help resist resistance.
1.Ray, S., Maitra, A., Biswas, A., Panjikar, S., Mondal, J., Anand R.*, Functional Insights into the Mode of DNA and Ligand Binding of the TetR
Family Regulator TylP from Streptomyces fradiae, J. Biol Chem. 2017, 292, 15301-15311.
- Bhukya, H., Bhujbalrao, R., Bitra, A., Anand, R.*; Structural and Functional Basis of Transcriptional Regulation by TetR Family Protein CprB from
- coelicolor A3(2), Nucleic Acids Res. 2014, 42(15):10122-33.
- Bhujbalrao, R., Anand, R.*, Deciphering Determinants in Ribosomal Methyltransferases that Confer Antimicrobial Resistance J. Am. Chem. Soc.
2019, 141 (4), 1425-1429.
About the speaker:
Prof. Ruchi Anand completed her PhD in 2004 from the Department of Chemistry and Chemical Biology at Cornell University, USA. After conducting postdoctoral research at Sloan Kettering and the University of Pennsylvania she joined IIT-Bombay in 2008 as an Assistant Professor. Her laboratory employs a combination of X-ray Crystallography, Cryo-EM, biochemical and biophysical tools to understand molecular mechanisms with implications to human health. Her current research interests follow a multipronged approach where she has contributed to two major areas, antimicrobial resistance and biosensors development. Towards the first goal of combating drug resistance she focuses both on unearthing enzyme systems that can serve as new therapeutic targets as well as is involved in understanding the origins of antibiotic resistance itself. Her recent work with bacterial transcription factors has paved the way to structure-guided development of biosensors for aromatic pollutants. Since 2016, she has been serving on the Editorial Advisory board for ACS Sensors. She was the recipient of the National Academy of Sciences Fellowship (FNASc) in 2019 and also won the National Women Bio-scientist Award, Department of Biotechnology, in 2018 and was awarded the CRSI bronze medal for 2020. She is also the recipient of the DBT-Wellcome Trust Alliance Senior Fellowship in 2020. She was admitted as a fellow to the Indian Academy of Science (IASc) in 2022.