From Synthetic Biology to Nanobiotechnology: Rational Antimicrobial Engineering Approaches for Combating Multidrug-Resistant Pathogens
Dr. Anushree Chatterjee Assistant Professor, Dept. of Chemical & Biological Engg, University of Colorado Boulder, USA
12th March 2018, Monday 3:00 PM, Seminar Hall, Dept of Chemical Engineering
Abstract:
The rapid rise of multidrug-resistant (MDR) superbugs and the declining antibiotic pipeline are serious challenges to global health. Rational design of antibiotics can accelerate development of effective therapies against MDR bacteria. In this talk, I will describe multi-pronged systems, synthetic biology, and nanobiotechnology based approaches being devised in our lab to rationally engineer therapeutics that can overcome antimicrobial resistance. Transcriptome studies in our lab have shown that, when exposed to antimicrobials, bacteria enter an “adaptive resistance” state by exploring multiple pathways sampling a dynamic gene regulatory space. We have developed an approach dubbed “Controlled Hindrance of Adaptation of OrganismS” or “CHAOS” to slow the evolution of antibiotic resistance by interfering with processes involved in adaptive resistance. Using CRISPR based technology, we rationally engineer library of synthetic genetic devices for multiplexed activation and inhibition of native gene expression of key essential and stress-response gene networks. Here we show that CHAOS approach leads to predominant negative epistasis with severe loss of fitness during adaptation to a range of toxins, including disinfectants and antibiotics, and eventual “slowing” down of bacteria's ability to adapt. To translate our findings into the clinical setting, we engineer antisense therapeutics that can block translation of any desired gene in a pathogen-specific manner for targeted inhibition. Using this approach we are building a Facile Accelerated Specific Therapeutic (FAST) platform for the accelerated development of novel antibiotics against MDR bacterial clinical isolates as well as any emergent bacterial threats. Finally, I will also present development of a unique semiconductor material based quantum dot-antibiotic (QD ABx) which, when activated by stimuli, release reactive oxygen species to eliminate a broad range of MDR bacterial clinical isolates including methicillin-resistant Staphylococcus aureus, extended-spectrum β-lactamase producing Klebsiella pneumoniae and Salmonella typhimurium, and carbapenem-resistant Escherichia coli. The CHAOS, FAST and QD Abx platforms presented in this talk offer novel approaches for impeding evolution of antibiotic resistance, developing new antibiotics, as well as re-sensitizing antibiotic-resistant pathogens to traditional therapies employed at the clinical setting.
Brief Bio:
Dr. Anushree Chatterjee is an Assistant Professor of Chemical and Biological Engineering at University of Colorado Boulder. Prior to joining UC Boulder, she was a postdoctoral research fellow at the Theoretical Biology and Biophysics group at Los Alamos National Laboratory studying gene regulation of hepatitis C virus. She completed her Ph.D. in Chemical engineering at the University of Minnesota on understanding molecular mechanisms of antibiotic resistance transfer in clinical superbugs. She completed her Bachelor and Master of Technology in Chemical Engineering from Indian Institute of Technology Delhi. The overarching goal of her research is to develop strategies for rationally engineering next-generation smart antimicrobials that can eliminate multi-drug resistant superbugs, with the ultimate goal of creating therapies that can evade evolution of drug-resistance in microbes. To achieve this goal her lab uses a combination of interdisciplinary approaches including synthetic biology, systems biology, and nanoengineering to design smart therapeutics. Anushree is the founder of the Antibiotic Regeneration Consortium which involves streamlining academic labs across the globe towards accelerated discovery and development of antibiotics. Anushree's research has been featured by academic and federal institutions such as the Material Research Society, Faculty of 1000, and the National Science Foundation, as well as popular national and international media outlets including BBC, CGTN America, and Voice of America. Anushree has received the DARPA Young Faculty Award, ACS Infectious Diseases Young Investigator Award, New Inventor of the Year award, the prestigious William M. keck Foundation grant award. She has also been named as one of the highly-prolific authors by ACS Infectious Diseases. She is the associate editor at Frontiers in Bioengineering and Biotechnology. She has also co-founded a Biotech startup company.