Chapter 11 : Regulation of Lipopolysaccharide Modifications and Antimicrobial Peptide Resistance

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Lipopolysaccharide (LPS) is the major component of the outer membrane of gram-negative bacteria and consists of three distinct structural domains: lipid A, a nonrepeating “core” oligosaccharide, and a distal repeated O-antigen polysaccharide. This chapter discusses the structure of the three regions, in order, as they extend out from the outer membrane, focusing on regulated alterations, modifications, and/or substitutions. The biosynthetic enzymes are either constitutively active or regulated by a variety of two-component regulatory systems, including PhoR/PhoB, PmrA/PmrB and/or PhoP/PhoQ. Deletion of IpxT in resulted in an increase in sensitivity to the cationic antimicrobial peptides (AMPs) polymyxin B, although experiments elucidating roles for lpxT in overall pathogenesis have yet to be undertaken. The chapter explores the regulation of one particular modification, that of phosphorylcholine (ChoP), on and lipooligosaccharide (LOS). Regulation of LPS core biosynthesis is not well understood, although some of the regulatory mechanisms for biosynthesis of Kdo and inner and outer core are emerging. The current evidence based on genetic and biophysical interaction studies of the Lpt proteins supports the transenvelope model. Further studies into the regulation of LPS should help provide a link between signals in the environment and the resulting outer membrane composition that are likely to have the most impact on host-pathogen interactions.

Citation: Ernst R, Powell D, Hittle L, GOLDBERG J, KINTZ E. 2013. Regulation of Lipopolysaccharide Modifications and Antimicrobial Peptide Resistance , p 209-238. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch11
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Figure 1

Schematic representation of modifications of terminal residues of lipid A. The diagram shows the possible modifications outside of the terminal residues of lipid A. Chemical groups are color coded by the enzyme responsible for their action; a plus sign indicates an addition to the base structure, and a minus sign indicates a removal. Under each enzyme is the regulatory system that controls each its action; an upward-pointing arrow indicates a positive regulator, and a downward-pointing arrow indicates a negative regulator. doi:10.1128/9781555818524.ch11f1

Citation: Ernst R, Powell D, Hittle L, GOLDBERG J, KINTZ E. 2013. Regulation of Lipopolysaccharide Modifications and Antimicrobial Peptide Resistance , p 209-238. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch11
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Figure 2

Pathway for the synthesis of Kdo. KdsD converts dribulose 5-phosphate to d-arabinose 5-phosphate. d-Arabinose 5-phosphate and phosphoenolpyruvate are combined by KdsA to form Kdo 8-phosphate. KdsC cleaves Kdo 8-phosphate to Kdo and inorganic phosphate. KdsB mediates the reaction of Kdo and CTP to form the activated sugar CMP-Kdo and PP. This active sugar is added to lipid IV in the inner membrane. doi:10.1128/9781555818524.ch11f2

Citation: Ernst R, Powell D, Hittle L, GOLDBERG J, KINTZ E. 2013. Regulation of Lipopolysaccharide Modifications and Antimicrobial Peptide Resistance , p 209-238. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch11
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Figure 3

Structures of LPS core. Structures of known inner and outer cores for serovar Typhimurium (A), K-12 (B), and R1 (C), R2 (D), R3 (E), and R4 (F). All genes with known/proposed activities are indicated with gray arrows at the sites of activity. Adapted from A. Silipo and A. Molinaro, 2010. doi:10.1128/9781555818524.ch11f3

Citation: Ernst R, Powell D, Hittle L, GOLDBERG J, KINTZ E. 2013. Regulation of Lipopolysaccharide Modifications and Antimicrobial Peptide Resistance , p 209-238. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch11
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Figure 4

Genetic organization of LPS core and LPS transport genes. (A) K-12 operon and known promoters. All promoters are indicated with interacting sigma factors. Genes for LPS transport are in white; the gene, part of the cation antiporter family, is shown in dark blue, and inner core genes are shown in black. (B) K-12 and operons with the gene and indicated promoters. Promoters are labeled with interacting sigma factors; promoters in black indicate active promoters, while blue promoters have not been proven active. Genes implicated in O-antigen synthesis are displayed in white, outer core genes are shown in blue, and inner core genes are shown in black. doi:10.1128/9781555818524.ch11f4

Citation: Ernst R, Powell D, Hittle L, GOLDBERG J, KINTZ E. 2013. Regulation of Lipopolysaccharide Modifications and Antimicrobial Peptide Resistance , p 209-238. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch11
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Figure 5

Structure and visualization of LPS. (A) The typical gram-negative membrane is comprised of the inner membrane, the periplasm, and the outer membrane. The inner membrane is a phospholipid bilayer with integral and peripheral membrane proteins. (B) Representation of LPS structure showing the O antigen in blue, core in purple, and lipid A in yellow. Phosphates are shown as black circles. (C) LPS from Typhimurium strain 14028s and its isogenic Δ mutant. The lower-molecularweight bands demonstrate the banding pattern associated with increasing O-antigen side chains. The loss of long chain lengths due to the absence of is evident in the deletion mutant strain. Since is still contained in the genome of both strains, the very long chain length is still detected at the top of the gel. LPS was detected using Salmonella O Antiserum Factor 4 from Difco Laboratories. doi:10.1128/9781555818524.ch11f5

Citation: Ernst R, Powell D, Hittle L, GOLDBERG J, KINTZ E. 2013. Regulation of Lipopolysaccharide Modifications and Antimicrobial Peptide Resistance , p 209-238. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch11
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Figure 6

O-antigen loci from different gram-negative bacteria. Organizations of loci were obtained from the Genome home of NCBI (http://www.ncbi.nlm.nih.gov/sites/genome). Strains are as follows: PAO1; Typhimurium LT2, and 2a str 301. Locus tag numbers are provided underneath genes at the beginning and end of the operons. For reference, some of the other O-antigen-associated genes are as follows: , = PA4999 and = PA0938; Typhimurium, () = STM1332 and (second gene) = STM0589; and , = SF3666. doi:10.1128/9781555818524.ch11f6

Citation: Ernst R, Powell D, Hittle L, GOLDBERG J, KINTZ E. 2013. Regulation of Lipopolysaccharide Modifications and Antimicrobial Peptide Resistance , p 209-238. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch11
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Figure 7

Wzy-dependent pathway for O-antigen synthesis and transfer across the inner membrane. The diagram shows that O antigens are synthesized on the Und-P and transferred via the Wzx, O-antigen flippase. The Wzy, O-antigen polymerase, extends the chains, the length of which is controlled by the Wzz O-antigen regulator. (Adapted from ) doi:10.1128/9781555818524.ch11f7

Citation: Ernst R, Powell D, Hittle L, GOLDBERG J, KINTZ E. 2013. Regulation of Lipopolysaccharide Modifications and Antimicrobial Peptide Resistance , p 209-238. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch11
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Figure 8

ABC transporter-dependent pathway for transfer across the inner membrane. The diagram shows the transfer of the Und- P-linked O antigen across the inner membrane by the ABC transporter, Wzm and Wzt. (Adapted from ) doi:10.1128/9781555818524.ch11f8

Citation: Ernst R, Powell D, Hittle L, GOLDBERG J, KINTZ E. 2013. Regulation of Lipopolysaccharide Modifications and Antimicrobial Peptide Resistance , p 209-238. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch11
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Figure 9

Diagram of the two proposed LptA transport mechanisms. In both models, MsbA transports the lipid A-core across the inner membrane. The completed Und-linked O antigen is transferred to the lipid A-core via the WaaL, O-antigen ligase (not shown). The left model shows that LptA docks with LptC and picks up the lipid A-core-O antigen and transports it across the periplasmic space, where it docks with the LptDE complex before being translocated across the outer membrane. In the right model, LptA oligomerizes to form a scaffold that allows the LPS to be transported across the periplasmic space. (Adapted from ) doi:10.1128/9781555818524.ch11f9

Citation: Ernst R, Powell D, Hittle L, GOLDBERG J, KINTZ E. 2013. Regulation of Lipopolysaccharide Modifications and Antimicrobial Peptide Resistance , p 209-238. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch11
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Table 1

Enzymes responsible for modification of lipid A

Citation: Ernst R, Powell D, Hittle L, GOLDBERG J, KINTZ E. 2013. Regulation of Lipopolysaccharide Modifications and Antimicrobial Peptide Resistance , p 209-238. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch11

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