Structure–Activity Relationships of Novel Tryptamine-Based Inhibitors of Bacterial Transglycosylase

Penicillin-binding proteins represent
well-established, validated, and still very promising targets for
the design and development of new antibacterial agents. The transglycosylase
domain of penicillin-binding proteins is especially important, as
it catalyzes polymerization of glycan chains, using the peptidoglycan
precursor lipid II as a substrate. On the basis of the previous discovery
of a noncovalent small-molecule inhibitor of transglycosylase activity,
we systematically explored the structure–activity relationships
of these tryptamine-based inhibitors. The main aim was to reduce the
nonspecific cytotoxic properties of the initial hit compound and concurrently
to retain the mode of its inhibition. A focused library of tryptamine-based
compounds was synthesized, characterized, and evaluated biochemically.
The results presented here show the successful reduction of the nonspecific
cytotoxicity, and the retention of the inhibition of transglycosylase
enzymatic activity, as well as the ability of these compounds to bind
to lipid II and to have antibacterial actions.