In Vivo Activity\nProfiling of Biosynthetic Darobactin\nD22 against Critical Gram-Negative Pathogens

In recent years, naturally occurring darobactins have\nemerged as\na promising compound class to combat infections caused by critical\nGram-negative pathogens. In this study, we describe the in vivo evaluation\nof derivative D22, a non-natural biosynthetic darobactin analogue\nwith significantly improved antibacterial activity. We found D22 to\nbe active in vivo against key critical Gram-negative human pathogens,\nas demonstrated in murine models of Pseudomonas aeruginosa thigh infection, Escherichia coli peritonitis/sepsis, and urinary tract infection (UTI). Furthermore,\nwe observed the restored survival of Acinetobacter\nbaumannii-infected embryos in a zebrafish infection\nmodel. These in vivo proof-of-concept (PoC) in diverse models of infection\nagainst highly relevant pathogens, including drug-resistant isolates,\nhighlight the versatility of darobactins in the treatment of bacterial\ninfections and show superiority of D22 over the natural darobactin\nA. Together with a favorable safety profile, these findings pave the\nway for further optimization of the darobactin scaffold toward the\ndevelopment of a novel antibiotic.