Covalent Proteomimetic Inhibitor of the Bacterial FtsQB Divisome Complex

The use of antibiotics is threatened by the emergence
and spread
of multidrug-resistant strains of bacteria. Thus, there is a need
to develop antibiotics that address new targets. In this respect,
the bacterial divisome, a multi-protein complex central to cell division,
represents a potentially attractive target. Of particular interest
is the FtsQB subcomplex that plays a decisive role in divisome assembly
and peptidoglycan biogenesis in E. coli. Here, we report the structure-based design of
a macrocyclic covalent inhibitor derived from a periplasmic region
of FtsB that mediates its binding to FtsQ. The bioactive conformation
of this motif was stabilized by a customized cross-link resulting
in a tertiary structure mimetic with increased affinity for FtsQ.
To increase activity, a covalent handle was incorporated, providing
an inhibitor that impedes the interaction between FtsQ and FtsB irreversibly. The covalent inhibitor reduced the growth of an outer
membrane-permeable E. coli strain,
concurrent with the expected loss of FtsB localization, and also affected
the infection of zebrafish larvae by a clinical E.
coli strain. This first-in-class inhibitor of a divisome
protein–protein interaction highlights the potential of proteomimetic
molecules as inhibitors of challenging targets. In particular, the
covalent mode-of-action can serve as an inspiration for future antibiotics
that target protein–protein interactions.