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.

Type II Fatty Acid Synthesis Is Essential for the Replication of Chlamydia trachomatis

“…First, FASII supplies the fatty acids required for the synthesis of membrane phospholipids, and second, FASII generates the 3-hydroxy fatty acids required for LOS synthesis. Previous work showed that the selective inhibition of LOS synthesis at the LpxC step permitted the proliferation of C. trachomatis within its cytoplasmic inclusion but blocked the terminal differentiation of RBs into EBs (10). If FASII is only required for generating 3-hydroxy fatty acids for LOS synthesis and the bacterium obtains its phospholipids from the host, then AFN-1252 inhibition would have the same effect on the infection cycle as a LOS inhibitor.…”

“…The outer membrane of C. trachomatis is decorated with a similar lipooligosaccharide (LOS) that contains 18 and 20 carbon 3-hydroxy fatty acids (7)(8)(9). The inhibition of LOS biosynthesis in C. trachomatis does not block RB proliferation but does prevent the differentiation of RB into EB, resulting in the accumulation of noninfectious RBs within the chlamydial inclusion (10). Thus, one function of FASII would be to provide these 3-hydroxy fatty acids for LOS synthesis in C. trachomatis, but it is unknown whether FASII is needed for phospholipid synthesis.…”

Colistin-Resistant, Lipopolysaccharide-Deficient Acinetobacter baumannii Responds to Lipopolysaccharide Loss through Increased Expression of Genes Involved in the Synthesis and Transport of Lipoproteins, Phospholipids, and Poly-β-1,6- N -Acetylglucosamine

“…However, viable, lipid A-deficient lpxA mutants have been constructed by directed mutagenesis in Neisseria meningitidis and Moraxella catarrhalis (38,49). Chlamydia trachomatis, treated with various LpxC small-molecule inhibitors, was shown recently to replicate in the reticulate body form while lacking LPS (33). The loss of lipid A, and therefore LPS, in N. meningitidis resulted in the reduced expression of surfaceexposed lipoproteins and altered outer membrane (OM) phospholipid composition, with LPS-deficient cells displaying preference for short-chain saturated fatty acids (48,55).…”

Lipopolysaccharide-Binding Alkylpolyamine DS-96 Inhibits Chlamydia trachomatis Infection by Blocking Attachment and Entry

“…Other studies have used Chlamydia LOS as a target for disruption of the developmental cycle, and various functions have been proposed (19,30). Fadel and Eley postulated a general role of LOS in Chlamydia infectivity (19).…”

“…After several rounds of replication, RBs asynchronously transform into EBs and are released by host cell lysis or extrusion (29). Recently, Nguyen et al used a chemical inhibitor of lipid A biosynthesis to demonstrate the crucial role of chlamydial LOS in proper conversion of RBs into infectious EBs (30). Interestingly, inhibition of LOS synthesis had little effect on RB replication, highlighting the importance of LOS in EB function.…”