| Literature DB >> 33949190 |
Hao Zhang1, Hao-Chi Hsu2, Shoshanna C Kahne3, Ryoma Hara4, Wenhu Zhan1, Xiuju Jiang1, Kristin Burns-Huang1, Tierra Ouellette1, Toshihiro Imaeda4, Rei Okamoto4, Masanori Kawasaki4, Mayako Michino4, Tzu-Tshin Wong4, Akinori Toita4, Takafumi Yukawa4, Francesca Moraca5, Jeremie Vendome5, Priya Saha1, Kenjiro Sato4, Kazuyoshi Aso4, John Ginn4, Peter T Meinke4, Michael Foley4, Carl F Nathan1, K Heran Darwin3, Huilin Li2, Gang Lin1.
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.Entities:
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Year: 2021 PMID： 33949190 PMCID： PMC8194371 DOI： 10.1021/acs.jmedchem.1c00296
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446