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Prodrug defiance reveals logic-based strategies for treating bacterial resistance

biorxiv. 2019; 
Brandon Alexander Holt, Isabel Curro, Gabriel A. Kwong
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Biochemicals Tobacco Etch Virus protease (TEVp), along with its substrate and buffer was obtained from Anaspec, Inc. (Fremont, CA). Activity RFU measurements were normalized to time 0 measurement, and as such represent fold change in signal. Outer Membrane Protease T (i.e., OmpT, Protease 7) was purchased from Lifespan Biosciences (Seattle, WA). OmpT fluorescent peptide substrate was custom ordered from Genscript (Piscataway, NJ). Get A Quote

摘要

Classifying the mechanisms of antibiotic failure has led to the development of new treatment strategies for killing bacteria. Among the currently described mechanisms – which include resistance, persistence and tolerance – we propose defiance as a subclass of antibiotic failure specific to prodrugs. Using locked antimicrobial peptides (AMP) that are activated by bacterial proteases as a prototypic prodrug, we observe that although treatment eliminates bacteria across the vast majority of environmental conditions (e.g., temperature, concentration of growth nutrients), bacteria spontaneously switch from susceptibility to defiance under conditions that alter the competing rates between bacterial proliferation ... More

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