Thermally activated antibiotic production by probiotic bacteria for pathogen elimination
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Engineered bacterial therapeutics is a rapidly emerging field in which bacteria are genetically engineered to produce and deliver therapeutic compounds at the body site of use. They offer the advantages of being able to produce biopharmaceutical drugs on the spot and control drug release time and dosage through genetic switches to treat a variety of diseases, including infections, inflammatory diseases, and cancer. However, a major challenge in the field is achieving drug production rates for effectively treating diseases. This is especially true when combining genetic switches with heterologous gene expression. This study presents an expression strategy to overcome this challenge as part of developing thermo-switchable production of a novel antibiotic, darobactin, in probiotic Escherichia coli Nissle 1917. While thermo-switchable promoters produced ineffective levels of darobactin, the T7 promoter enabled production of pathogen-inhibitory levels although it was highly leaky. Thus, parts from both switches were combined to create a thermo-amplifier circuit that shows no detectable leakiness below 37 °C and releases sufficient darobactin at 40°C to inhibit the growth of a critically prioritized Pseudomonas aeruginosa pathogen.
