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1. (CSDB ID: 22297) | report error |
| R-3HOMyr-(1-3)-+ | Myr-(1-3)-R-3HOMyr-(1-3)-+ ?%P---P--1)-+ | | | | Lau-(1-3)-R-3HOMyr-(1-2)-b-D-GlcpN-(1-6)-a-D-GlcpN | | P-4)-+ | | R-3HOMyr-(1-2)-+ | Show graphically |
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Escherichia coli K-12
(NCBI TaxID 83333,
species name lookup)
]
uga.edu>Gram-negative bacteria have a unique cell surface that can be modified to maintain bacterial fitness in diverse environments. A well-defined example is the modification of the lipid A component of lipopolysaccharide (LPS), which promotes resistance to polymyxin antibiotics and antimicrobial peptides. In many organisms, such modifications include the addition of the amine-containing constituents 4-amino-4-deoxy-l-arabinose (l-Ara4N) and phosphoethanolamine (pEtN). Addition of pEtN is catalyzed by EptA, which uses phosphatidylethanolamine (PE) as its substrate donor, resulting in production of diacylglycerol (DAG). DAG is then quickly recycled into glycerophospholipid (GPL) synthesis by the DAG kinase A (DgkA) to produce phosphatidic acid, the major GPL precursor. Previously, we hypothesized that loss of DgkA recycling would be detrimental to the cell when LPS is heavily modified. Instead, we found that DAG accumulation inhibits EptA activity, preventing further degradation of PE, the predominant GPL of the cell. However, DAG inhibition of pEtN addition results in complete loss of polymyxin resistance. Here, we selected for suppressors to find a mechanism of resistance independent of DAG recycling or pEtN modification. Disrupting the gene encoding the adenylate cyclase, cyaA, fully restored antibiotic resistance without restoring DAG recycling or pEtN modification. Supporting this, disruptions of genes that reduce CyaA-derived cAMP formation (e.g., ptsI) or disruption of the cAMP receptor protein, Crp, also restored resistance. We found that loss of the cAMP-CRP regulatory complex was necessary for suppression and that resistance arises from a substantial increase in l-Ara4N-modified LPS, bypassing the need for pEtN modification. IMPORTANCE Gram-negative bacteria can alter the structure of their LPS to promote resistance to cationic antimicrobial peptides, including polymyxin antibiotics. Polymyxins are considered last-resort antibiotics for treatment against multidrug-resistant Gram-negative organisms. Here, we explore how changes in general metabolism and carbon catabolite repression pathways can alter LPS structure and influence polymyxin resistance.
Lipopolysaccharide, lipid A, phosphoethanolamine, outer membrane, aminoarabinose, cAMP receptor protein, cyclic AMP
Structure type: oligomer|
2. (CSDB ID: 22338) | report error |
| ?%Subst-(1-2)-+ | -3)-b-D-GlcpNAc-(1-3)-b-D-6didoHepp-(1- | ?%Subst-(1-7)-+ Subst = H or O-methyl phosphamide = SMILES {1}OP(OC)(N)=O | Show graphically |
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Campylobacter jejuni HS:4
(Ancestor NCBI TaxID 197,
species name lookup)
]biochem.wisc.edu>; F.M. Raushel <rausheltamu.edu>Campylobacter jejuni is a human pathogen and the leading cause of food poisoning in the United States and Europe. Surrounding the exterior surface of this bacterium is a capsular polysaccharide (CPS) that consists of a repeating sequence of common and unusual carbohydrate segments. At least 10 different heptose sugars have thus far been identified in the various strains of C. jejuni. The accepted biosynthetic pathway for the construction of the 6-deoxy-heptoses begins with the 4,6-dehydration of GDP-d-glycero-d-manno-heptose by a dehydratase, followed by an epimerase that racemizes C3 and/or C5 of the product GDP-6-deoxy-4-keto-d-lyxo-heptose. In the final step, a C4-reductase catalyzes the NADPH reduction of the resulting 4-keto product. However, in some strains and serotypes of C. jejuni, there are two separate C4-reductases with different product specificities in the gene cluster for CPS formation. Five pairs of these tandem C4-reductases were isolated, and the catalytic properties were ascertained. In four out of five cases, one of the two C4-reductases is able to catalyze the isomerization of C3 and C5 of GDP-6-deoxy-4-keto-d-lyxo-heptose, in addition to the catalysis of the reduction of C4, thus bypassing the requirement for a separate C3/C5-isomerase. In each case, the 3'-end of the gene for the first C4-reductase contains a poly-G tract of 8-10 guanine residues that may be used to control the expression and/or catalytic activity of either C4-reductase. The three-dimensional structure of the C4-reductase from serotype HS:15, which only does a reduction of C4, was determined to 1.45 A resolution in the presence of NADPH and GDP.
serotype, capsular polysaccharide, Campylobacter jejuni, 6-deoxy-heptoses, C4-reductases
Structure type: polymer chemical repeating unit|
3. (CSDB ID: 26009) | report error |
| R-3HOMyr-(1-3)-+ | Lau-(1-3)-R-3HOMyr-(1-2)-+ /Variants 1/-+ | | | | /Variants 0/-b-D-GlcpN-(1-6)-a-D-GlcpN | | Myr-(1-3)-R-3HOMyr-(1-3)-+ | | ?%Pam-(1-3)-R-3HOMyr-(1-2)-+ /Variants 0/ is: ?%b-L-Arap4N-(1--P--4)-- OR (exclusively) EtN-(1-0)-?%P---P--4)- /Variants 1/ is: ?%b-L-Arap4N-(1--P--1)-- OR (exclusively) EtN-(1-0)-?%P---P--1)- | Show graphically |
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Escherichia coli K-12
(NCBI TaxID 83333,
species name lookup)
]uga.edu>Gram-negative bacteria have a unique cell surface that can be modified to maintain bacterial fitness in diverse environments. A well-defined example is the modification of the lipid A component of lipopolysaccharide (LPS), which promotes resistance to polymyxin antibiotics and antimicrobial peptides. In many organisms, such modifications include the addition of the amine-containing constituents 4-amino-4-deoxy-l-arabinose (l-Ara4N) and phosphoethanolamine (pEtN). Addition of pEtN is catalyzed by EptA, which uses phosphatidylethanolamine (PE) as its substrate donor, resulting in production of diacylglycerol (DAG). DAG is then quickly recycled into glycerophospholipid (GPL) synthesis by the DAG kinase A (DgkA) to produce phosphatidic acid, the major GPL precursor. Previously, we hypothesized that loss of DgkA recycling would be detrimental to the cell when LPS is heavily modified. Instead, we found that DAG accumulation inhibits EptA activity, preventing further degradation of PE, the predominant GPL of the cell. However, DAG inhibition of pEtN addition results in complete loss of polymyxin resistance. Here, we selected for suppressors to find a mechanism of resistance independent of DAG recycling or pEtN modification. Disrupting the gene encoding the adenylate cyclase, cyaA, fully restored antibiotic resistance without restoring DAG recycling or pEtN modification. Supporting this, disruptions of genes that reduce CyaA-derived cAMP formation (e.g., ptsI) or disruption of the cAMP receptor protein, Crp, also restored resistance. We found that loss of the cAMP-CRP regulatory complex was necessary for suppression and that resistance arises from a substantial increase in l-Ara4N-modified LPS, bypassing the need for pEtN modification. IMPORTANCE Gram-negative bacteria can alter the structure of their LPS to promote resistance to cationic antimicrobial peptides, including polymyxin antibiotics. Polymyxins are considered last-resort antibiotics for treatment against multidrug-resistant Gram-negative organisms. Here, we explore how changes in general metabolism and carbon catabolite repression pathways can alter LPS structure and influence polymyxin resistance.
Lipopolysaccharide, lipid A, phosphoethanolamine, outer membrane, aminoarabinose, cAMP receptor protein, cyclic AMP
Structure type: oligomer|
4. (CSDB ID: 27065) | report error |
| -3)-a-L-6dgulHepp-(1-3)-a-L-Araf-(1- | Show graphically |
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Campylobacter jejuni HS:15
(Ancestor NCBI TaxID 197,
species name lookup)
]biochem.wisc.edu>; F.M. Raushel <rausheltamu.edu>Campylobacter jejuni is a human pathogen and the leading cause of food poisoning in the United States and Europe. Surrounding the exterior surface of this bacterium is a capsular polysaccharide (CPS) that consists of a repeating sequence of common and unusual carbohydrate segments. At least 10 different heptose sugars have thus far been identified in the various strains of C. jejuni. The accepted biosynthetic pathway for the construction of the 6-deoxy-heptoses begins with the 4,6-dehydration of GDP-d-glycero-d-manno-heptose by a dehydratase, followed by an epimerase that racemizes C3 and/or C5 of the product GDP-6-deoxy-4-keto-d-lyxo-heptose. In the final step, a C4-reductase catalyzes the NADPH reduction of the resulting 4-keto product. However, in some strains and serotypes of C. jejuni, there are two separate C4-reductases with different product specificities in the gene cluster for CPS formation. Five pairs of these tandem C4-reductases were isolated, and the catalytic properties were ascertained. In four out of five cases, one of the two C4-reductases is able to catalyze the isomerization of C3 and C5 of GDP-6-deoxy-4-keto-d-lyxo-heptose, in addition to the catalysis of the reduction of C4, thus bypassing the requirement for a separate C3/C5-isomerase. In each case, the 3'-end of the gene for the first C4-reductase contains a poly-G tract of 8-10 guanine residues that may be used to control the expression and/or catalytic activity of either C4-reductase. The three-dimensional structure of the C4-reductase from serotype HS:15, which only does a reduction of C4, was determined to 1.45 A resolution in the presence of NADPH and GDP.
serotype, capsular polysaccharide, Campylobacter jejuni, 6-deoxy-heptoses, C4-reductases
Structure type: polymer chemical repeating unit| New query | Export IDs | Home | Help |
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