Biophysical Society Thematic Meeting | Stockholm 2022

Physical and Quantitative Approaches to Overcome Antibiotic Resistance

Poster Abstracts

26-POS Board 26 A HIGH-THROUGHPUT APPROACH TO THE DISCOVERY OF NOVEL DNA INTERCALATING ANTIMICROBIAL AND ANTINEOPLASTIC DRUGS Chandrashekhar U Murade 1 ; Samata Chaudhuri 1 ; Ibtissem Nabti 1 ; Hala Fahs 1 ; Fatima Refai 1 ; Xin Xie 1 ; Yanthe E Pearson 1 ; Kristin C Gunsalus 1,2 ; George T. Shubeita 1 ; 1 New York University Abu Dhabi, Abu Dhabi, United Arab Emirates 2 New York University, New York, NY, USA Molecules that bind DNA by intercalating its bases remain among the most potent antimicrobials and cancer therapies due to their interference with DNA-processing proteins. To accelerate the discovery of novel intercalating drugs, we designed a Fluorescence Resonance Energy Transfer (FRET)-based probe that reports on DNA intercalation, allowing rapid and sensitive screening of chemical libraries in a high-throughput format. We demonstrate that the method correctly identifies known DNA intercalators in approved drug libraries and discover previously unreported intercalating compounds. When introduced in mammalian cells, the oligonucleotide based probe rapidly distributes in the cytosol and nucleus, allowing direct imaging of the dynamics of drug entry and its interaction with DNA in its native environment. This enabled us to directly correlate the potency of intercalators in killing cultured cancer cells with the ability of the drug to penetrate the cell membrane. The combined capability of the single probe to identify intercalators in vitro and follow their function in vivo can play a valuable role in accelerating the discovery of novel DNA-intercalating drugs or repurposing approved ones.

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