ALTERING THE TARGET - MICHAEL ACCEPTOR SMALL MOLECULES DERIVED FROM CHLORAMPHENICOL WHICH ACT AS NOVEL COVALENT ANTIBIOTICS

Covalent antibiotics have proved to be successful therapies for a broad spectrum of bacteria and have made a major positive impact on human health. Although nearly 30% of drugs on the market act via a covalent mechanism of action, the majority of those were not designed as covalent inhibitors and were discovered later to act via a covalent mechanism.

The increasing number of drug candidates with a covalent mechanism of action progressing through clinical trials or being approved by the FDA has increased significantly in recent years, and created evident challenges for characterizing and optimizing these inhibitors. While the design of selective covalent inhibitors is conceptually very attractive, it is in practice hard to achieve. That is because it is difficult to strike the right balance between reactivity and selectivity.

We recently designed and synthesized a collection of chlormaphenicol-derived α,β-unsaturated carbonyl systems that act as Michael acceptors and serve as covalent drugs for the inhibition of cell wall biosynthesis. Two ketone derivatives were found to have a good antimicrobial activity against Gram positive bacteria. By using LC-MS analysis we established that these two compounds covalently bind to cysteine residues which are also found in the catalytic domain of MurA that is involved in bacterial cell wall biosynthesis and is a known target for the development of antimicrobial agents.