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(367d) From Synthetic Biology to Nano Biotechnology: Rational Antimicrobial Engineering Approaches Towards Combating Drug-Resistant Pathogens

Chatterjee, A., University of Colorado Boulder
The rapid rise of drug-resistant superbugs and the declining antibiotic pipeline are serious challenges to global health. In this talk, I will describe multi-pronged systems, synthetic biology and nanobiotechnology approaches being devised in our lab to engineer antimicrobials 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 investigate these adaptive pathways by controllably up-regulating and down-regulating the expression of genes known to be involved in bacterial tolerance. We employ emerging synthetic biology techniques to investigate gene regulatory networks involved in controlling adaptive resistance. Using CRISPR based technology, we rationally engineer library of synthetic genetic devices to activate and inhibit native gene expression of key essential gene and stress-response networks. Here we show that in the presence of these synthetic perturbations, significant control over bacterial fitness can be achieved during adaptation to sub-minimal inhibitory concentrations of a range of toxins, including disinfectants and antibiotics. Moreover, we employ this approach to perturb expression of multiple genes simultaneously, and observe predominant negative epistasis with severe loss in fitness. To translate our findings in to 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 I will demonstrate a platform for accelerated development of novel antibiotics against multi-drug resistant (MDR) bacterial clinical isolates as well as any emergent bacterial threats. Finally, I will also present an engineered nanoparticle-based therapeutic strategy using quantum dots 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 techniques presented in this talk offer a novel approach for both impeding the intrinsic adaptive pathways leading to antibiotic resistance, and re-sensitizing antibiotic resistant pathogens to traditional therapies employed at the clinical setting.