Abstract # 1
Ruchi Anand - Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, Maharashtra, INDIA
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:
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Singh et al., ACS Chem. Biol. 2022 Apr; 17(4):829-839.
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Bhujbalrao R, and Anand R, J. Am. Chem. Soc. 2019 Jan; 141(4):1425-1429.
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Bhujbalrao R, et al., J. Biol. Chem. 2022 Aug; 298(8):102208.
Abstract # 2
Arindam Chowdhury - Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, Maharashtra, INDIA
Stochastic photoluminescence (PL) intermittency (blinking) between bright and dark intensity levels (blinking) has been long recognized to be characteristic of single emitters. Apart from fluorescent molecules, a variety of quantum-confined semiconductor nanocrystals also exhibit PL blinking. In contrast, such PL instability is seldom reported beyond nanoscale dimensions as spatiotemporally uncorrelated intensity fluctuations are expected to be averaged out over the ensemble. Interestingly, upon investigation of organo-metal halide perovskite (OHP) crystals where charge carriers are not confined, we discovered a bizarre phenomenon where entire micron-sized (CH3NH3)PbBr3 disks/films undergo multi-level blinking (flickering) on top of a base emission. Intriguingly, such photoinduced optical instability was found to be spatially-synchronous across each micro-crystal, indicating effective communication amongst carriers photogenerated at distal locations of each crystal. Moreover, we often observe such spatiotemporal correlation in blinking/flickering to be diverse over both space and time, which makes it even more challenging to interpret. We propose a model involving few highly efficient metastable traps coupled with correlated carrier migration – excited carriers can recombine non-radiatively within a certain zone of influence of a transient quencher. In this lecture, I will discuss plausible mechanisms and factors responsible for spatiotemporally (in)homogeneous optical instabilities in perovskites, which may be relevant in terms of their usage as active layers in solar PV or light emissive devices.
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