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The Inhibition of Lipid A Biosynthesis—The Antidote Against Superbugs?

After many years of success in the battle against infectious diseases, ground is being lost in this fight with the worldwide increasing appearance of “superbugs,” which are resistant to most antibiotics in clinical use. The impact of superbugs on the older population, healthcare‐associated patients or patients with a compromised immune system is highly worrisome since no treatment options are available in some cases, especially for Gram‐negative pathogens. Efforts are currently devoted to develop novel chemical entities with new mechanisms of action that can inactivate unexplored or underexplored bacterial objectives and to better understand bacterial behavior. The present article highlights the therapeutic potential of the enzymes involved in the biosynthesis of lipid A, which is the lipidic component of lipopolysaccharide—a lipid‐anchored complex carbohydrate and a well‐designed natural barrier to protect Gram‐negative bacteria from external agents, such as antibiotics. An overview of the state‐of‐the‐art inhibitors currently available along with the biochemical and structural knowledge of the enzyme/ligand complexes available is provided. This insight will contribute to the rational design of the next generation of inhibitors or the development of new ones for those promising targets for which inhibitors have not yet been developed.