Macrocyclic Peptides that Selectively Inhibit the Mycobacterium tuberculosis Proteasome

Area of Science:

• Biochemistry
• Microbiology
• Drug Discovery

Background:

• Tuberculosis (TB) treatment requires at least 6 months.
• Latent Mycobacterium tuberculosis (Mtb) is drug-tolerant.
• Targeting nonreplicating Mtb may shorten TB treatment.

Purpose of the Study:

• Identify novel drug targets for nonreplicating Mtb.
• Develop compounds that inhibit the Mtb proteasome (Mtb20S).
• Evaluate Mtb20S inhibitors for anti-TB therapeutic potential.

Main Methods:

• Synthesized and screened macrocyclic peptides for Mtb20S inhibition.
• Determined cocrystal structure of Mtb20S with macrocycle 6.
• Assessed the effect of Mtb20S inhibition on nonreplicating Mtb.

Main Results:

• Developed potent and selective Mtb20S-targeting macrocyclic peptides.
• Macrocycle 6 demonstrated species selectivity over human proteasomes.
• Inhibition of Mtb20S by macrocycle 6 killed nonreplicating Mtb under stress.

Conclusions:

• Mtb proteasome is a viable target for anti-TB drug development.
• Macrocyclic peptides show promise as novel TB therapeutics.
• Targeting Mtb20S may offer a strategy to shorten TB treatment durations.