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Facile Accelerated Specific Therapeutic (FAST) Platform to Counter Multidrug-Resistant Bacteria

Kristen A. Eller, Thomas R. Aunins, Colleen M. Courtney, Jocelyn K. Campos, Peter B. Otoupal, Keesha E. Erickson, Nancy E. Madinger, View ORCID ProfileAnushree Chatterjee
doi: https://doi.org/10.1101/850313
Kristen A. Eller
1Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO 80303
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Thomas R. Aunins
1Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO 80303
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Colleen M. Courtney
1Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO 80303
5Biotechnology & Bioengineering Department, Sandia National Laboratories, P.O. Box 969, Livermore, CA 94550
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Jocelyn K. Campos
1Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO 80303
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Peter B. Otoupal
1Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO 80303
6Joint Bioenergy Institute, 5885 Hollis St. Emeryville, California 94608
7Joint Bioenergy Institute Biomass Science and Conversion Technologies, Sandia National Laboratories, P.O. Box 969, Livermore, CA 94550
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Keesha E. Erickson
1Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO 80303
4Theoretical Biology & Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545
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Nancy E. Madinger
2Division of Infectious Diseases, University of Colorado Denver, Aurora, CO 80045
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Anushree Chatterjee
1Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO 80303
3Biomedical Engineering, University of Colorado Boulder, Boulder, CO 80303
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  • ORCID record for Anushree Chatterjee
  • For correspondence: chatterjee@colorado.edu
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ABSTRACT

Multidrug-resistant (MDR) bacteria pose a grave concern to global health. This problem is further aggravated by a lack of new and effective antibiotics and countermeasure platforms that can sustain the creation of novel antimicrobials in the wake of new outbreaks or evolution of resistance to antibiotics. To address this, we have developed a Facile Accelerated Specific Therapeutic (FAST) platform that can develop effective therapies against MDR bacteria within a week. Our FAST platform combines four essential modules- design, build, test, and delivery-of drug development cycle. The design module comprises a bioinformatics toolbox that predicts sequence-specific peptide nucleic acids (PNAs) that target non-traditional pathways and genes of bacteria in minutes. The build module constitutes in-situ synthesis and validation of selected PNAs in less than four days and efficacy testing within a day. As a proof of concept, these PNAs were tested against MDR clinical isolates. Here we tested Enterobacteriaceae including carbapenem-resistant Escherichia coli, extended-spectrum beta-lactamase (ESBL) Klebsiella pneumoniae, New Delhi Metallo-beta-lactamase-1 carrying Klebsiella pneumoniae and MDR Salmonella enterica. PNAs showed significant growth inhibition for 82% of treatments, with nearly 18% of the treatments leading to more than 97% decrease. Further, these PNAs are capable of potentiating antibiotic activity in the clinical isolates despite presence of cognate resistance genes. Finally, FAST offers a novel delivery approach to overcome limited transport of PNAs into mammalian cells to clear intracellular infections. This method relies on repurposing the bacterial Type III secretion system in conjunction with a kill switch that is effective at eliminating 99.6% of an intracellular Salmonella infection in human epithelial cells. Our findings demonstrate the potential of the FAST platform in treating MDR bacteria in a rapid and effective manner.

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Posted November 21, 2019.
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Facile Accelerated Specific Therapeutic (FAST) Platform to Counter Multidrug-Resistant Bacteria
Kristen A. Eller, Thomas R. Aunins, Colleen M. Courtney, Jocelyn K. Campos, Peter B. Otoupal, Keesha E. Erickson, Nancy E. Madinger, Anushree Chatterjee
bioRxiv 850313; doi: https://doi.org/10.1101/850313
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Facile Accelerated Specific Therapeutic (FAST) Platform to Counter Multidrug-Resistant Bacteria
Kristen A. Eller, Thomas R. Aunins, Colleen M. Courtney, Jocelyn K. Campos, Peter B. Otoupal, Keesha E. Erickson, Nancy E. Madinger, Anushree Chatterjee
bioRxiv 850313; doi: https://doi.org/10.1101/850313

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