Macrocyclic Peptides that Selectively Inhibit the Mycobacterium tuberculosis Proteasome

Treatment of tuberculosis (TB) currently
takes at least 6 months.
Latent Mycobacterium tuberculosis (Mtb)
is phenotypically tolerant to most anti-TB drugs. A key hypothesis
is that drugs that kill nonreplicating (NR) Mtb may shorten treatment
when used in combination with conventional drugs. The Mtb proteasome
(Mtb20S) could be such a target because its pharmacological inhibition
kills NR Mtb and its genetic deletion renders Mtb unable to persist
in mice. Here, we report a series of macrocyclic peptides that potently
and selectively target the Mtb20S over human proteasomes, including
macrocycle 6. The cocrystal structure of macrocycle 6 with Mtb20S revealed structural bases for the species selectivity.
Inhibition of 20S within Mtb by 6 dose dependently led
to the accumulation of Pup-tagged GFP that is degradable but resistant
to depupylation and death of nonreplicating Mtb under nitrosative
stress. These results suggest that compounds of this class have the
potential to develop as anti-TB therapeutics.