With the threat of a postantibiotic era looming, there is great interest in developing new therapeutics to take their place. A recent analysis published in The Lancet reported that antibiotic resistance contributed to 5.85 million deaths in 2021 and estimated that this number could increase to more than 10 million per year by 2050 [1]. With the rapid rise in antibiotic-resistant infections and a dwindling pipeline for the development of new and more effective antibiotics, there is an urgent need for innovative solutions.

One promising alternative to antibiotics is bacteriophage (phage) therapy. Phages are viruses that infect bacteria and kill the infected cell to release their progeny. Since their discovery in the early 1900s, scientists have explored the use of these bacterial predators for targeting and eradicating bacterial infections in humans, animals, and plants. In 1919, French-Canadian microbiologist Félix d'Hérelle successfully used phage preparations to treat children with bacterial dysentery, and through to the 1930s, phage therapy was used in many countries [2], and several American pharmaceutical companies manufactured commercial phage products for therapeutic use [3]. While the widespread availability of effective antibiotics made phage therapy fall out of favor in Western countries, it continued to be used in Eastern Europe and Russia. However, highly variable success rates and poor documentation of use have led to some controversy about its effectiveness [4].

In recent years, interest in phage therapy has been revived due to increasing antibiotic resistance and the recognition of the importance of the human microbiome in health and disease. In the last 5 years, there have been a number of well-documented cases where phage therapy was used to successfully treat life-threatening infections where antibiotics had failed 5, 6, 7, 8. In particular, clinical phage therapy has proven effective against multidrug-resistant Klebsiella pneumoniae infections: patients with primary sclerosing cholangitis who received a tailored phage cocktail showed marked reductions in liver inflammation and overall disease severity [9]. While promising, phage therapy faces several challenges that hinder its mainstream clinical use, including the narrow host range of most naturally occurring phages and the potential for bacterial resistance to arise. However, advances in high-throughput sequencing, genetic engineering, and synthetic biology offer new tools to address these barriers. Here, we review recent advances in phage biology and engineering that are contributing to the development of designer phages that can be used to precisely target disease-causing antibiotic-resistant bacteria.