New Cyclic Peptides Selectively Kill Dormant Tuberculosis Bacteria by Targeting Their Proteasome | Research

The takeaway

A series of macrocyclic peptides potently and selectively inhibit the Mycobacterium tuberculosis proteasome over human proteasomes, killing nonreplicating TB bacteria that are resistant to conventional drugs.

Selective TB proteasome inhibition
Macrocycle 6 potently inhibits the Mycobacterium tuberculosis proteasome while sparing human proteasomes, killing dormant bacteria that evade standard antibiotics

What the researchers found

Macrocycle 6 selectively inhibits Mtb20S, leading to the death of nonreplicating Mtb.

Why it matters

Targeting the Mtb proteasome could significantly improve tuberculosis treatment by effectively addressing drug-resistant forms of the bacteria. This research opens new avenues for developing faster-acting anti-TB therapies.

How the study worked

The study involved synthesizing macrocyclic peptides and assessing their effects on Mtb proteasome inhibition and bacterial viability.

What this study cannot tell us

The study primarily focuses on in vitro results, and further research is needed to confirm efficacy in vivo and in clinical settings.

How to read the evidence

This is a preclinical medicinal chemistry study with in vitro bacterial killing data and structural biology validation. While the results are promising and mechanistically detailed (including co-crystal structure), no animal efficacy data or human studies are presented.

When this study was published

Published in 2021 in the Journal of Medicinal Chemistry, this study established a new class of anti-TB peptides. Follow-up optimization and in vivo testing would be expected in subsequent years.

The bigger picture

Tuberculosis remains one of the world's deadliest infectious diseases, killing over a million people annually. The biggest challenge is treating latent or dormant TB, which requires months of antibiotic therapy. The Mtb proteasome is a validated drug target because it's essential for bacterial persistence, and macrocyclic peptides offer a way to hit this target with species selectivity — a critical advantage since human proteasome inhibitors (used in cancer) would be too toxic for long-term TB treatment. This work advances the growing field of peptide-based anti-infective therapeutics.

Questions still open

Can these macrocyclic peptides achieve adequate drug levels inside human cells where TB bacteria hide?
How effective would proteasome inhibitors be when combined with first-line TB drugs in animal models?
Could resistance to proteasome-targeting peptides develop, and if so, through what mechanisms?

Common questions

Why is dormant tuberculosis so hard to treat?

TB bacteria can enter a dormant, nonreplicating state inside the body where they become tolerant to most antibiotics, which typically work by disrupting processes in actively dividing cells. This is why TB treatment takes 6+ months — to catch bacteria as they occasionally reactivate. Drugs that can directly kill dormant bacteria could dramatically shorten treatment time.

What are macrocyclic peptides and why are they useful as drugs?

Macrocyclic peptides are ring-shaped molecules made from amino acids. Their cyclic structure makes them more stable than linear peptides and allows them to bind tightly and selectively to specific protein targets. In this case, their structure enables them to fit precisely into the TB proteasome's active site while not fitting into the human version, achieving the selectivity needed for a safe drug.

Read the original research

Macrocyclic Peptides that Selectively Inhibit the Mycobacterium tuberculosis Proteasome.

Journal of medicinal chemistry, 64(9), 6262-6272

View on PubMed ↗Publisher’s paper ↗

Citation

Zhang, Hao; Hsu, Hao-Chi; Kahne, Shoshanna C; Hara, Ryoma; Zhan, Wenhu; Jiang, Xiuju; Burns-Huang, Kristin; Ouellette, Tierra; Imaeda, Toshihiro; Okamoto, Rei; Kawasaki, Masanori; Michino, Mayako; Wong, Tzu-Tshin; Toita, Akinori; Yukawa, Takafumi; Moraca, Francesca; Vendome, Jeremie; Saha, Priya; Sato, Kenjiro; Aso, Kazuyoshi; Ginn, John; Meinke, Peter T; Foley, Michael; Nathan, Carl F; Darwin, K Heran; Li, Huilin; Lin, Gang. (2021). Macrocyclic Peptides that Selectively Inhibit the Mycobacterium tuberculosis Proteasome.. Journal of medicinal chemistry, 64(9), 6262-6272. https://doi.org/10.1021/acs.jmedchem.1c00296