Antibiotic class with potent in vivo activity targeting lipopolysaccharide synthesis in Gram-negative bacteria

The ready availability of effective antibiotics underpins all of modern medicine. The ever-increasing spread of antimicrobial resistance continuously degrades the efficacy of existing antibiotics, thus requiring the development of innovative compounds and strategies simply to maintain the status quo. The lack of novel antibiotics to address this problem, particularly for difficult-to-treat Gram-negative infections, has been well documented. Here we describe the development of a unique antibiotic class targeting lipopolysaccharide synthesis, from an initial hit, to compounds with favorable drug-like properties and potent in vivo activity. This work verifies that the target of these compounds, LpxH in Gram-negative bacteria, is a viable target for antibiotics, and that the chemical series that we have investigated is promising for further development.