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Targeting bacteria via iminoboronate chemistry of amine-presenting lipids.

Bandyopadhyay A, McCarthy KA, Kelly MA, Gao J - Nat Commun (2015)

Bottom Line: Here we show that targeted recognition of lipids can be realized by selectively modifying the lipid of interest via covalent bond formation.By targeting phosphatidylethanolamine and lysylphosphatidylglycerol, the two lipids enriched on bacterial cell surfaces, the iminoboronate chemistry allows potent labelling of Gram-positive bacteria even in the presence of 10% serum, while bypassing mammalian cells and Gram-negative bacteria.The covalent strategy for lipid recognition should be extendable to other important membrane lipids.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Merkert Chemistry Center, Boston College, 2609 Beacon Street, Chestnut Hill, Massachuetts 02467, USA.

ABSTRACT
Synthetic molecules that target specific lipids serve as powerful tools for understanding membrane biology and may also enable new applications in biotechnology and medicine. For example, selective recognition of bacterial lipids may give rise to novel antibiotics, as well as diagnostic methods for bacterial infection. Currently known lipid-binding molecules primarily rely on noncovalent interactions to achieve lipid selectivity. Here we show that targeted recognition of lipids can be realized by selectively modifying the lipid of interest via covalent bond formation. Specifically, we report an unnatural amino acid that preferentially labels amine-presenting lipids via iminoboronate formation under physiological conditions. By targeting phosphatidylethanolamine and lysylphosphatidylglycerol, the two lipids enriched on bacterial cell surfaces, the iminoboronate chemistry allows potent labelling of Gram-positive bacteria even in the presence of 10% serum, while bypassing mammalian cells and Gram-negative bacteria. The covalent strategy for lipid recognition should be extendable to other important membrane lipids.

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Covalent recognition of membrane lipids(a) Structures of the major membrane lipids from mamallian (SM, PC) and bacterial (PE, PG, Lys-PG) cells. PE and PS exist in mammalian cells as minority lipids. SM: sphingomyelin; PC: phosphatidylcholine; PE: phosphatidylethanolamine; PG: phosphatidylglycerol; Lys-PG: lysylphosphatidylglycerol; PS: phosphatidylserine. (b) Illustration of the iminoboronate chemistry for targeting PE on bacterial cell surfaces.
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Figure 1: Covalent recognition of membrane lipids(a) Structures of the major membrane lipids from mamallian (SM, PC) and bacterial (PE, PG, Lys-PG) cells. PE and PS exist in mammalian cells as minority lipids. SM: sphingomyelin; PC: phosphatidylcholine; PE: phosphatidylethanolamine; PG: phosphatidylglycerol; Lys-PG: lysylphosphatidylglycerol; PS: phosphatidylserine. (b) Illustration of the iminoboronate chemistry for targeting PE on bacterial cell surfaces.

Mentions: It is increasingly clear that membrane lipids do not merely provide a physical barrier for a cell; instead they play active roles in regulating numerous processes in cell physiology and disease.1 To support the diverse functions of a membrane, the composite lipids, while maintaining the common feature of amphiphilicity, do vary in their chemical structures to give a complex lipidome (Fig. 1a).2,3 The lipid composition of a membrane has significant ramifications in biology. For example, it is well known that the plasma membranes of bacterial and mammalian cells display distinct compositions of lipids: while a mammalian cell membrane primarily consists of phosphatidylcholine (PC) and sphingomyelin (SM), bacterial cells display highly enriched phosphatidylethanolamine (PE) and phosphatidylglycerol (PG).4,5 In addition, some bacteria species present a lysine modified PG (Lys-PG, Fig. 1a) in high percentages as a resistance mechanism to cationic antibiotics.6 Synthetic molecules that specifically target bacterial lipids may give rise to new imaging methods of bacterial infection, as well as novel solutions to the antibiotic resistance problem. The critical importance of lipids also manifests in the subcellular distribution of certain lipids in mammalian cells, a change of which may alter the homeostasis of important signaling proteins.7,8 To further elucidate the diverse roles of membrane lipids, it is highly desirable to have molecular probes that specifically target a lipid of interest as well. Currently known lipid-targeting agents, which are primarily lipid-binding proteins and their synthetic mimetics, achieve lipid recognition by employing networks of noncovalent interactions, such as hydrogen bonds and salt bridges.9,10 It remains to be seen whether membrane lipids can be selectively recognized by covalently targeting their unique chemical structure and reactivity with synthetic molecules.


Targeting bacteria via iminoboronate chemistry of amine-presenting lipids.

Bandyopadhyay A, McCarthy KA, Kelly MA, Gao J - Nat Commun (2015)

Covalent recognition of membrane lipids(a) Structures of the major membrane lipids from mamallian (SM, PC) and bacterial (PE, PG, Lys-PG) cells. PE and PS exist in mammalian cells as minority lipids. SM: sphingomyelin; PC: phosphatidylcholine; PE: phosphatidylethanolamine; PG: phosphatidylglycerol; Lys-PG: lysylphosphatidylglycerol; PS: phosphatidylserine. (b) Illustration of the iminoboronate chemistry for targeting PE on bacterial cell surfaces.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4363082&req=5

Figure 1: Covalent recognition of membrane lipids(a) Structures of the major membrane lipids from mamallian (SM, PC) and bacterial (PE, PG, Lys-PG) cells. PE and PS exist in mammalian cells as minority lipids. SM: sphingomyelin; PC: phosphatidylcholine; PE: phosphatidylethanolamine; PG: phosphatidylglycerol; Lys-PG: lysylphosphatidylglycerol; PS: phosphatidylserine. (b) Illustration of the iminoboronate chemistry for targeting PE on bacterial cell surfaces.
Mentions: It is increasingly clear that membrane lipids do not merely provide a physical barrier for a cell; instead they play active roles in regulating numerous processes in cell physiology and disease.1 To support the diverse functions of a membrane, the composite lipids, while maintaining the common feature of amphiphilicity, do vary in their chemical structures to give a complex lipidome (Fig. 1a).2,3 The lipid composition of a membrane has significant ramifications in biology. For example, it is well known that the plasma membranes of bacterial and mammalian cells display distinct compositions of lipids: while a mammalian cell membrane primarily consists of phosphatidylcholine (PC) and sphingomyelin (SM), bacterial cells display highly enriched phosphatidylethanolamine (PE) and phosphatidylglycerol (PG).4,5 In addition, some bacteria species present a lysine modified PG (Lys-PG, Fig. 1a) in high percentages as a resistance mechanism to cationic antibiotics.6 Synthetic molecules that specifically target bacterial lipids may give rise to new imaging methods of bacterial infection, as well as novel solutions to the antibiotic resistance problem. The critical importance of lipids also manifests in the subcellular distribution of certain lipids in mammalian cells, a change of which may alter the homeostasis of important signaling proteins.7,8 To further elucidate the diverse roles of membrane lipids, it is highly desirable to have molecular probes that specifically target a lipid of interest as well. Currently known lipid-targeting agents, which are primarily lipid-binding proteins and their synthetic mimetics, achieve lipid recognition by employing networks of noncovalent interactions, such as hydrogen bonds and salt bridges.9,10 It remains to be seen whether membrane lipids can be selectively recognized by covalently targeting their unique chemical structure and reactivity with synthetic molecules.

Bottom Line: Here we show that targeted recognition of lipids can be realized by selectively modifying the lipid of interest via covalent bond formation.By targeting phosphatidylethanolamine and lysylphosphatidylglycerol, the two lipids enriched on bacterial cell surfaces, the iminoboronate chemistry allows potent labelling of Gram-positive bacteria even in the presence of 10% serum, while bypassing mammalian cells and Gram-negative bacteria.The covalent strategy for lipid recognition should be extendable to other important membrane lipids.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Merkert Chemistry Center, Boston College, 2609 Beacon Street, Chestnut Hill, Massachuetts 02467, USA.

ABSTRACT
Synthetic molecules that target specific lipids serve as powerful tools for understanding membrane biology and may also enable new applications in biotechnology and medicine. For example, selective recognition of bacterial lipids may give rise to novel antibiotics, as well as diagnostic methods for bacterial infection. Currently known lipid-binding molecules primarily rely on noncovalent interactions to achieve lipid selectivity. Here we show that targeted recognition of lipids can be realized by selectively modifying the lipid of interest via covalent bond formation. Specifically, we report an unnatural amino acid that preferentially labels amine-presenting lipids via iminoboronate formation under physiological conditions. By targeting phosphatidylethanolamine and lysylphosphatidylglycerol, the two lipids enriched on bacterial cell surfaces, the iminoboronate chemistry allows potent labelling of Gram-positive bacteria even in the presence of 10% serum, while bypassing mammalian cells and Gram-negative bacteria. The covalent strategy for lipid recognition should be extendable to other important membrane lipids.

Show MeSH
Related in: MedlinePlus