title: Lipooligosaccharide is required for the generation of infectious elementary bodies in Chlamydia trachomatis.
abstract: Lipopolysaccharides (LPS) and lipooligosaccharides (LOS) are the main lipid components of bacterial outer membranes and are essential for cell viability in most Gram-negative bacteria. Here we show that small molecule inhibitors of LpxC [UDP-3-O-(R-3-hydroxymyristoyl)-GlcNAc deacetylase], the enzyme that catalyzes the first committed step in the biosynthesis of lipid A, block the synthesis of LOS in the obligate intracellular bacterial pathogen Chlamydia trachomatis. In the absence of LOS, Chlamydia remains viable and establishes a pathogenic vacuole ("inclusion") that supports robust bacterial replication. However, bacteria grown under these conditions were no longer infectious. In the presence of LpxC inhibitors, replicative reticulate bodies accumulated in enlarged inclusions but failed to express selected late-stage proteins and transition to elementary bodies, a Chlamydia developmental form that is required for invasion of mammalian cells. These findings suggest the presence of an outer membrane quality control system that regulates Chlamydia developmental transition to infectious elementary bodies and highlights the potential application of LpxC inhibitors as unique class of antichlamydial agents.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Bidong D
authors.initials: BD
authors.lastname: Nguyen
authors.forename: Doreen
authors.initials: D
authors.lastname: Cunningham
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Liang
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Toone
authors.forename: Christian R H
authors.initials: CR
authors.lastname: Raetz
authors.forename: Pei
authors.initials: P
authors.lastname: Zhou
authors.forename: Raphael H
authors.initials: RH
authors.lastname: Valdivia
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D002690:Chlamydia Infections; D002692:Chlamydia trachomatis / Q000166:cytology / Q000472:pathogenicity* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D008050:Lipid A / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure
chemical_list: D001426:Bacterial Proteins; D008050:Lipid A; D008070:Lipopolysaccharides; C023023:lipid-linked oligosaccharides; D000581:Amidohydrolases