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Updated: Nov 6, 2025
System for Efficacy and Cytotoxicity Screening of Inhibitors Targeting Intracellular Mycobacterium tuberculosis
Published on: April 5, 2017
Macrocyclic Peptides that Selectively Inhibit the Mycobacterium tuberculosis Proteasome
Hao Zhang1, Hao-Chi Hsu2, Shoshanna C Kahne3
1Department of Microbiology & Immunology, Weill Cornell Medicine, 1300 York Avenue, New York, New York 10065, United States.
Abstract:
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.
Insights
New macrocyclic peptides target the Mycobacterium tuberculosis proteasome (Mtb20S), killing nonreplicating bacteria. This discovery could lead to shorter tuberculosis (TB) treatment regimens.
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.
