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Enterobactin-mediated delivery of β-lactam antibiotics enhances antibacterial activity against pathogenic Escherichia coli.

Zheng T, Nolan EM - J. Am. Chem. Soc. (2014)

Bottom Line: Under conditions of iron limitation, these siderophore-modified antibiotics provide enhanced antibacterial activity against Escherichia coli strains, including uropathogenic E. coli CFT073 and UTI89, enterohemorrhagic E. coli O157:H7, and enterotoxigenic E. coli O78:H11, compared to the parent β-lactams.Moreover, Ent-Amp and Ent-Amx selectively kill E. coli CFT073 co-cultured with other bacterial species such as Staphylococcus aureus, and Ent-Amp exhibits low cytotoxicity against human T84 intestinal cells in both the apo and iron-bound forms.These studies demonstrate that the native enterobactin platform provides a means to effectively deliver antibacterial cargo across the outer membrane permeability barrier of Gram-negative pathogens utilizing enterobactin for iron acquisition.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.

ABSTRACT
The design, synthesis, and characterization of enterobactin-antibiotic conjugates, hereafter Ent-Amp/Amx, where the β-lactam antibiotics ampicillin (Amp) and amoxicillin (Amx) are linked to a monofunctionalized enterobactin scaffold via a stable poly(ethylene glycol) linker are reported. Under conditions of iron limitation, these siderophore-modified antibiotics provide enhanced antibacterial activity against Escherichia coli strains, including uropathogenic E. coli CFT073 and UTI89, enterohemorrhagic E. coli O157:H7, and enterotoxigenic E. coli O78:H11, compared to the parent β-lactams. Studies with E. coli K-12 derivatives defective in ferric enterobactin transport reveal that the enhanced antibacterial activity observed for this strain requires the outer membrane ferric enterobactin transporter FepA. A remarkable 1000-fold decrease in minimum inhibitory concentration (MIC) value is observed for uropathogenic E. coli CFT073 relative to Amp/Amx, and time-kill kinetic studies demonstrate that Ent-Amp/Amx kill this strain more rapidly at 10-fold lower concentrations than the parent antibiotics. Moreover, Ent-Amp and Ent-Amx selectively kill E. coli CFT073 co-cultured with other bacterial species such as Staphylococcus aureus, and Ent-Amp exhibits low cytotoxicity against human T84 intestinal cells in both the apo and iron-bound forms. These studies demonstrate that the native enterobactin platform provides a means to effectively deliver antibacterial cargo across the outer membrane permeability barrier of Gram-negative pathogens utilizing enterobactin for iron acquisition.

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Structures of enterobactin (1,Ent) and a generalizedenterobactin–cargo conjugate.
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fig1: Structures of enterobactin (1,Ent) and a generalizedenterobactin–cargo conjugate.

Mentions: Both native siderophores and synthetic siderophore mimicshave been evaluated as platforms for therapeutic development.20−25,59,60 In the clinic, the native siderophore desferrioxamineB is used for iron-chelation therapy in patients with iron overload.Several antibiotic small molecules found in Nature called “sideromycins”provide inspiration for synthetic siderophore–antibioticconjugates.61 The sideromycins are secondarymetabolites comprised of a siderophore moiety and a toxic cargo;the siderophore portion targets sideromycins to bacterial strainsexpressing the appropriate siderophore receptor. Microcin E492m,a siderophore–antibiotic conjugate produced by a clinicalisolate of Klebsiella pneumoniae, is an 84-residueantibacterial peptide with a glucosylated enterobactin (Ent, Figure 1) derivative attached to its C-terminus that exhibitsenhanced antibacterial activity against strains expressing the enterobactinreceptor FepA.62 From the standpoints ofantibacterial activity and therapeutic potential, studies of syntheticsiderophore–antibiotic conjugates have provided thecommunity with mixed results, causing some skepticism about the potentialof siderophore-based approaches despite the successful utilizationof such molecules by Nature.


Enterobactin-mediated delivery of β-lactam antibiotics enhances antibacterial activity against pathogenic Escherichia coli.

Zheng T, Nolan EM - J. Am. Chem. Soc. (2014)

Structures of enterobactin (1,Ent) and a generalizedenterobactin–cargo conjugate.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4353011&req=5

fig1: Structures of enterobactin (1,Ent) and a generalizedenterobactin–cargo conjugate.
Mentions: Both native siderophores and synthetic siderophore mimicshave been evaluated as platforms for therapeutic development.20−25,59,60 In the clinic, the native siderophore desferrioxamineB is used for iron-chelation therapy in patients with iron overload.Several antibiotic small molecules found in Nature called “sideromycins”provide inspiration for synthetic siderophore–antibioticconjugates.61 The sideromycins are secondarymetabolites comprised of a siderophore moiety and a toxic cargo;the siderophore portion targets sideromycins to bacterial strainsexpressing the appropriate siderophore receptor. Microcin E492m,a siderophore–antibiotic conjugate produced by a clinicalisolate of Klebsiella pneumoniae, is an 84-residueantibacterial peptide with a glucosylated enterobactin (Ent, Figure 1) derivative attached to its C-terminus that exhibitsenhanced antibacterial activity against strains expressing the enterobactinreceptor FepA.62 From the standpoints ofantibacterial activity and therapeutic potential, studies of syntheticsiderophore–antibiotic conjugates have provided thecommunity with mixed results, causing some skepticism about the potentialof siderophore-based approaches despite the successful utilizationof such molecules by Nature.

Bottom Line: Under conditions of iron limitation, these siderophore-modified antibiotics provide enhanced antibacterial activity against Escherichia coli strains, including uropathogenic E. coli CFT073 and UTI89, enterohemorrhagic E. coli O157:H7, and enterotoxigenic E. coli O78:H11, compared to the parent β-lactams.Moreover, Ent-Amp and Ent-Amx selectively kill E. coli CFT073 co-cultured with other bacterial species such as Staphylococcus aureus, and Ent-Amp exhibits low cytotoxicity against human T84 intestinal cells in both the apo and iron-bound forms.These studies demonstrate that the native enterobactin platform provides a means to effectively deliver antibacterial cargo across the outer membrane permeability barrier of Gram-negative pathogens utilizing enterobactin for iron acquisition.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.

ABSTRACT
The design, synthesis, and characterization of enterobactin-antibiotic conjugates, hereafter Ent-Amp/Amx, where the β-lactam antibiotics ampicillin (Amp) and amoxicillin (Amx) are linked to a monofunctionalized enterobactin scaffold via a stable poly(ethylene glycol) linker are reported. Under conditions of iron limitation, these siderophore-modified antibiotics provide enhanced antibacterial activity against Escherichia coli strains, including uropathogenic E. coli CFT073 and UTI89, enterohemorrhagic E. coli O157:H7, and enterotoxigenic E. coli O78:H11, compared to the parent β-lactams. Studies with E. coli K-12 derivatives defective in ferric enterobactin transport reveal that the enhanced antibacterial activity observed for this strain requires the outer membrane ferric enterobactin transporter FepA. A remarkable 1000-fold decrease in minimum inhibitory concentration (MIC) value is observed for uropathogenic E. coli CFT073 relative to Amp/Amx, and time-kill kinetic studies demonstrate that Ent-Amp/Amx kill this strain more rapidly at 10-fold lower concentrations than the parent antibiotics. Moreover, Ent-Amp and Ent-Amx selectively kill E. coli CFT073 co-cultured with other bacterial species such as Staphylococcus aureus, and Ent-Amp exhibits low cytotoxicity against human T84 intestinal cells in both the apo and iron-bound forms. These studies demonstrate that the native enterobactin platform provides a means to effectively deliver antibacterial cargo across the outer membrane permeability barrier of Gram-negative pathogens utilizing enterobactin for iron acquisition.

Show MeSH
Related in: MedlinePlus