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Published on: June 10, 2020
The Small Molecule H89 Inhibits Chlamydia Inclusion Growth and Production of Infectious Progeny
Karissa J Muñoz1, Kevin Wang2, Lauren M Sheehan2
1Department of Developmental and Cell Biology, University of California, Irvine, California, USA.
Abstract:
Chlamydia is an obligate intracellular bacterium and the most common reportable cause of human infection in the United States. This pathogen proliferates inside a eukaryotic host cell, where it resides within a membrane-bound compartment called the chlamydial inclusion. It has an unusual developmental cycle, marked by conversion between a replicating form, the reticulate body (RB), and an infectious form, the elementary body (EB). We found that the small molecule H89 slowed inclusion growth and decreased overall RB replication by 2-fold but caused a 25-fold reduction in infectious EBs. This disproportionate effect on EB production was mainly due to a defect in RB-to-EB conversion and not to the induction of chlamydial persistence, which is an altered growth state. Although H89 is a known inhibitor of specific protein kinases and vesicular transport to and from the Golgi apparatus, it did not cause these anti-chlamydial effects by blocking protein kinase A or C or by inhibiting protein or lipid transport. Thus, H89 is a novel anti-chlamydial compound that has a unique combination of effects on an intracellular Chlamydia infection.
Insights
The small molecule H89 inhibits Chlamydia growth and significantly reduces infectious elementary body production by disrupting reticulate body to elementary body conversion. This compound offers a novel approach to treating intracellular Chlamydia infections.
Area of Science:
- Microbiology
- Cell Biology
- Infectious Diseases
Background:
- * *Chlamydia* is a common cause of human infection in the US, residing within host cells in a specialized compartment called the chlamydial inclusion.
- * *Chlamydia* exhibits a unique developmental cycle involving conversion between replicating reticulate bodies (RB) and infectious elementary bodies (EB).
Purpose of the Study:
- * To investigate the anti-chlamydial effects of the small molecule H89.
- * To determine the mechanism by which H89 impacts *Chlamydia* replication and development.
Main Methods:
- * Treatment of intracellular *Chlamydia* infections with the small molecule H89.
- * Analysis of inclusion growth, RB replication, and EB production.
- * Investigation of potential mechanisms including protein kinase inhibition and disruption of vesicular transport.
Main Results:
- * H89 slowed inclusion growth and reduced RB replication by 2-fold.
- * H89 caused a significant 25-fold reduction in infectious EB production.
- * The primary effect was a defect in RB-to-EB conversion, not chlamydial persistence induction.
- * H89's effects were independent of protein kinase A or C inhibition or blocked protein/lipid transport.
Conclusions:
- * H89 is a novel anti-chlamydial compound with a unique mechanism of action.
- * H89 disproportionately inhibits the production of infectious *Chlamydia* elementary bodies.
- * H89 represents a potential new therapeutic strategy for intracellular *Chlamydia* infections.
