IMB-BZ as an Inhibitor Targeting ESX-1 Secretion System to Control Mycobacterial Infection.

Abstract

BACKGROUND:

Resistance to anti-tuberculosis (TB) drugs is a major issue in TB control, and demands the discovery of new drugs targeting the virulence factor ESX-1.

METHODS:

We first established a high-throughput screen (HTS) assay for the discovery of ESX-1 secretion inhibitors. The positive hits were then evaluated for the potency of diminishing the survival of virulent mycobacteria and reducing bacterial virulence. We further investigated the probability of inducing drug resistance and the underlying mechanism using mycobacterial protein fragment complementation.

RESULTS:

A robust HTS assay was developed to identify small molecules that inhibit ESX-1 secretion without impairing bacterial growth in vitro. A hit named IMB-BZ specifically inhibits the secretion of CFP-10 and reduces virulence in an ESX-1-dependent manner, therefore resulting in significant reduction in intracellular and in vivo survival of mycobacteria. Blocking the CFP-10-EccCb1 interaction directly or indirectly underlies the inhibitory effect of IMB-BZ on the secretion of CFP-10. Importantly, our finding shows that the ESX-1 inhibitors pose low risk of drug resistance development by mycobacteria in vitro as compared with traditional anti-TB drugs, and exhibit high potency against chronic mycobacterial infection.

CONCLUSIONS:

Targeting ESX-1 may lead to the development of novel therapeutics for tuberculosis. IMB-BZ holds the potential for future development into a new anti-TB drug.

• Authors: Pingping Jia, Yi Zhang, Jian Xu, Mei Zhu, Shize Peng, Yongxin Zhang, Jianyuan Zhao, Xiaoyu Li, Kaixia Mi, Dan Yan, Yucheng Wang, Liyan Yu, Yu Lu, Hanping Shi, Shan Cen
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 225 Issue 4 Pg. 608-616 (02 15 2022) ISSN: 1537-6613 [Electronic] United States
• PMID: 34558604 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected].

Chemical References

• Antitubercular Agents
• Bacterial Proteins
• Type VII Secretion Systems

Topics

• Antitubercular Agents (pharmacology)
• Bacterial Proteins (metabolism)
• Humans
• Mycobacterium tuberculosis
• Tuberculosis (drug therapy)
• Type VII Secretion Systems (metabolism)
• Virulence