Related Experiment Video

Updated: Apr 22, 2026

System for Efficacy and Cytotoxicity Screening of Inhibitors Targeting Intracellular Mycobacterium tuberculosis
09:57

System for Efficacy and Cytotoxicity Screening of Inhibitors Targeting Intracellular Mycobacterium tuberculosis

Published on: April 5, 2017

8.1K

Anticytolytic screen identifies inhibitors of mycobacterial virulence protein secretion

Jan Rybniker1, Jeffrey M Chen2, Claudia Sala2

  • 1Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; 1(st) Department of Internal Medicine, University of Cologne, 50937 Cologne, Germany.

Cell Host & Microbe
|October 10, 2014
PubMed

Insights

Researchers identified novel compounds that inhibit Mycobacterium tuberculosis (Mtb) protein secretion, a key virulence factor. These inhibitors reduce Mtb

Area of Science:

  • Microbiology
  • Molecular Biology
  • Drug Discovery

Background:

  • Mycobacterium tuberculosis (Mtb) utilizes protein secretion systems, notably ESX-1, for intracellular survival and virulence.
  • The ESX-1 substrate EsxA is a major virulence determinant, inhibiting phagosome maturation and causing cell lysis, which facilitates pathogen spread.
  • Developing inhibitors of Mtb protein secretion is crucial for combating tuberculosis.

Purpose of the Study:

  • To identify novel small molecules that inhibit Mtb protein secretion.
  • To discover compounds that protect host cells from Mtb-induced damage without exhibiting direct bactericidal activity.
  • To elucidate the mechanisms of action for identified inhibitors and their impact on Mtb virulence factors.

Main Methods:

  • Development of a fibroblast survival assay to screen for inhibitors of Mtb-induced host cell lysis.
  • Selection of compounds that protect host cells and block EsxA secretion in vitro.
  • Macrophage-based assays to assess phagosome maturation and bacterial load reduction.
  • Target identification studies, including chemical genetics and biochemical assays, to pinpoint the molecular targets of hit compounds.

Main Results:

  • A fibroblast survival assay successfully identified compounds inhibiting Mtb protein secretion.
  • Hit compounds blocked EsxA secretion and promoted phagosome maturation in macrophages, leading to reduced bacterial loads.
  • Target identification revealed BTP15, an inhibitor of the histidine kinase MprB, which indirectly regulates ESX-1.
  • BBH7, a novel compound, was found to affect Mtb metal-ion homeostasis and identified zinc stress as an activator of EsxA secretion.

Conclusions:

  • The developed screening approach is effective for identifying inhibitors of Mtb protein secretion.
  • Inhibiting ESX-1-mediated secretion offers a promising strategy for developing new anti-tubercular therapeutics.
  • The discovery of BTP15 and BBH7, along with the identification of zinc stress as a regulatory signal, provides new avenues for therapeutic intervention against drug-resistant Mtb.

More Related Videos

Author Spotlight: Scalable Drug Screening Protocol for Efficient Discovery of M. abscessus Treatments07:50

Author Spotlight: Scalable Drug Screening Protocol for Efficient Discovery of M. abscessus Treatments

Published on: October 25, 2024

2.0K
A Microscopic Phenotypic Assay for the Quantification of Intracellular Mycobacteria Adapted for High-throughput/High-content Screening15:28

A Microscopic Phenotypic Assay for the Quantification of Intracellular Mycobacteria Adapted for High-throughput/High-content Screening

Published on: January 17, 2014

7.3K

Related Concept Videos

Inhibitors of Bacterial Protein Synthesis01:25

Inhibitors of Bacterial Protein Synthesis

Aminoglycosides constitute a highly potent class of bactericidal antibiotics that exert their antimicrobial effects by targeting the bacterial ribosome, specifically disrupting protein synthesis. These polycationic molecules consist of amino-modified sugars linked via glycosidic bonds to an aminocyclitol core such as 2-deoxystreptamine or streptamine. Their strong positive charges facilitate tight binding to the negatively charged phosphate backbone of ribosomal RNA (rRNA), primarily at the 16S...
93
Inhibitors of Bacterial DNA Synthesis01:28

Inhibitors of Bacterial DNA Synthesis

Bacterial pathogens depend on precise and efficient DNA replication to sustain infection. Two type II topoisomerases—DNA gyrase and topoisomerase IV—are critical to this process, as they resolve DNA supercoiling and unlink chromosomes during replication. Fluoroquinolones, synthetic derivatives of quinolones, exploit this mechanism by stabilizing the transient DNA–enzyme cleavage complex, preventing strand religation, and causing lethal double-strand breaks. These...
113
Inhibitors of Viral Protein Synthesis01:30

Inhibitors of Viral Protein Synthesis

Protein synthesis is indispensable for viral replication, as viruses lack the cellular machinery required for this process and must hijack the host's translational apparatus. In response, host cells deploy a critical innate immune defense involving interferons, specialized cytokines that play a central role in inhibiting viral propagation.Upon viral detection, infected cells release interferons that bind to receptors on adjacent uninfected cells, activating the JAK-STAT signaling pathway and...
50