Fosmidomycin, an inhibitor of isoprenoid synthesis, induces persistence in Chlamydia by inhibiting peptidoglycan assembly

English version

Autoři: Jessica A. Slade ^aff001; Mary Brockett ^aff002; Raghuveer Singh ^aff001; George W. Liechti ^aff002; Anthony T. Maurelli ^aff001
Působiště autorů: Emerging Pathogens Institute and Department of Environmental and Global Health, College of Public Health and Health Professions, University of Florida, Gainesville, Florida, United States of America ^aff001; Department of Microbiology and Immunology, F. Edward Hébert School of Medicine, Uniformed Services University, Bethesda, Maryland, United States of America ^aff002
Vyšlo v časopise: Fosmidomycin, an inhibitor of isoprenoid synthesis, induces persistence in Chlamydia by inhibiting peptidoglycan assembly. PLoS Pathog 15(10): e32767. doi:10.1371/journal.ppat.1008078
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008078

Souhrn

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 (Dxr_CT) 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 (Dxr_CT) in Escherichia coli under FSM exposure and in a conditionally lethal dxr mutant demonstrated that Dxr_CT 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.

Klíčová slova:

Antibiotics – Crystal structure – HeLa cells – Chlamydia – Chlamydia infection – Peptidoglycans – Isoprenoids

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