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Fosmidomycin, an inhibitor of isoprenoid synthesis, induces persistence in Chlamydia by inhibiting peptidoglycan assembly.
- Source :
-
PLoS pathogens [PLoS Pathog] 2019 Oct 17; Vol. 15 (10), pp. e1008078. Date of Electronic Publication: 2019 Oct 17 (Print Publication: 2019). - Publication Year :
- 2019
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Abstract
- The antibiotic, fosmidomycin (FSM) targets the methylerythritol phosphate (MEP) pathway of isoprenoid synthesis by inhibiting the essential enzyme, 1-deoxy-D-xylulose 5-phosphate reductoisomerase (Dxr) and is lethal to intracellular parasites and bacteria. The obligate intracellular bacterial pathogen, Chlamydia trachomatis, alternates between two developmental forms: the extracellular, infectious elementary body (EB), and the intracellular, replicative form called the reticulate body (RB). Several stressful growth conditions including iron deprivation halt chlamydial cell division and cause development of a morphologically enlarged, but viable form termed an aberrant body (AB). This phenotype constitutes the chlamydial developmental state known as persistence. This state is reversible as removal of the stressor allows the chlamydiae to re-enter and complete the normal developmental cycle. Bioinformatic analysis indicates that C. trachomatis encodes a homolog of Dxr, but its function and the requirement for isoprenoid synthesis in chlamydial development is not fully understood. We hypothesized that chlamydial Dxr (DxrCT) is functional and that the methylerythritol phosphate (MEP) pathway is required for normal chlamydial development. Thus, FSM exposure should be lethal to C. trachomatis. Overexpression of chlamydial Dxr (DxrCT) in Escherichia coli under FSM exposure and in a conditionally lethal dxr mutant demonstrated that DxrCT functions similarly to E. coli Dxr. When Chlamydia-infected cultures were exposed to FSM, EB production was significantly reduced. However, titer recovery assays, electron microscopy, and peptidoglycan labeling revealed that FSM inhibition of isoprenoid synthesis is not lethal to C. trachomatis, but instead induces persistence. Bactoprenol is a critical isoprenoid required for peptidoglycan precursor assembly. We therefore conclude that FSM induces persistence in Chlamydia by preventing bactoprenol production necessary for peptidoglycan precursor assembly and subsequent cell division.<br />Competing Interests: The authors have declared that no competing interests exist.
- Subjects :
- Aldose-Ketose Isomerases antagonists & inhibitors
Aldose-Ketose Isomerases genetics
Aldose-Ketose Isomerases metabolism
Cell Line, Tumor
Chlamydia Infections pathology
Chlamydia trachomatis enzymology
Chlamydia trachomatis physiology
Escherichia coli enzymology
Escherichia coli genetics
Escherichia coli metabolism
Fosfomycin pharmacology
HeLa Cells
Humans
Anti-Bacterial Agents pharmacology
Chlamydia trachomatis drug effects
Fosfomycin analogs & derivatives
Peptidoglycan biosynthesis
Terpenes metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7374
- Volume :
- 15
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- PLoS pathogens
- Publication Type :
- Academic Journal
- Accession number :
- 31622442
- Full Text :
- https://doi.org/10.1371/journal.ppat.1008078