The rising prevalence of antibiotic resistant microbial pathogens presents an ominous health and economic challenge to modern society. The discovery and large-scale development of antibiotic drugs in previous decades was transformational, providing cheap, effective treatment for what would previously have been a lethal infection. As microbial strains resistant to many or even all antibiotic drug treatments have evolved, there is an urgent need for new drugs or antimicrobial treatments to control these pathogens. The ability to sequence and mine the genomes of an increasing number of microbial strains from previously unexplored environments has the potential to identify new natural product antibiotic biosynthesis pathways. This coupled with the power of synthetic biology to generate new production chassis, biosensors and “weaponized” live cell therapeutics may provide new means to combat the rapidly evolving threat of drug resistant microbial pathogens. This review focuses on the application of synthetic biology to construct probiotic strains that have been endowed with functionalities allowing them to identify, compete with and in some cases kill microbial pathogens as well as stimulate host immunity. Weaponized probiotics may have the greatest potential for use against pathogens that infect the gastrointestinal tract: Vibrio cholerae, Staphylococcus aureus, Clostridium perfringens and Clostridioides difficile. The potential benefits of engineered probiotics are highlighted along with the challenges that must still be met before these intriguing and exciting new therapeutic tools can be widely deployed.

The discovery and application of antibiotic drugs is among the most significant accomplishments of medical science. Alexander Fleming’s discovery of penicillin (Fleming, 1929) and subsequent discovery and development of multiple classes of natural product antibiotics have been transformational to modern society. These compounds have yielded cheap and effective treatments for diseases caused by common bacterial infections that would previously have proven fatal. The advent of effective antibiotic drugs has made it possible to survive complex surgical procedures like open heart surgery and organ transplants and extended the average human life-span (Riley, 2005; Kaviani et al., 2020). The benefits of readily available antibiotic drugs have extended into agriculture and aquaculture, making it possible to increase productivity of farmed animals (Park et al., 1994; Patel et al., 2020).