Recent advances in the design and development of small molecules against Lpx enzymes for mitigating Pseudomonas aeruginosa infections

The emergence of infections caused by the gram-negative bacterium Pseudomonas aeruginosa is widely recognized as a major cause of nosocomial infections and antimicrobial resistance. In gram-negative bacteria such as P. aeruginosa, Lipid A helps maintain cell membrane integrity, and targeting its biosynthesis, known as the Raetz pathway, can be a strategic approach to control these infections. The set of Lpx enzymes involved in the synthesis of Lipid A serves as a potential target for inhibiton. This review outlines strategies for the design and development of small-molecule inhibitors of enzymes that inhibit bacterial growth and mitigate infection. In silico techniques and synthetic procedures have been employed to develop inhibitors targeting a specific enzyme. The presence of the UDP-GlcNAc group, acyl chain-binding group, five-membered ring, amide group, benzamide group, heteroatom, and fused rings is a key set of features that provides a basic scaffold for designing Lpx inhibitors. The structural characteristics of the receptor responsible for prominent ligand interactions have also been discussed, providing a foundation for the development of selective and potent inhibitors.