Selective Phenylimidazole-Based Inhibitors of the Mycobacterium tuberculosis Proteasome

Proteasomes
of pathogenic microbes have become attractive targets
for anti-infectives. Coevolving with its human host, Mycobacterium tuberculosis (Mtb) has developed mechanisms
to resist host-imposed nitrosative and oxidative stresses. Genetic
deletion or pharmacological inhibition of the Mtb proteasome (Mtb20S)
renders nonreplicating Mtb susceptible to reactive nitrogen species
in vitro and unable to survive in the lungs of mice, validating the
Mtb proteasome as a promising target for anti-Mtb agents. Using a
structure-guided and flow chemistry-enabled study of structure–activity
relationships, we developed phenylimidazole-based peptidomimetics
that are highly potent for Mtb20S. X-ray structures of selected compounds
with Mtb20S shed light on their selectivity for mycobacterial over
human proteasomes.