RRC ID 35498
Author Zheng T, Bullock JL, Nolan EM.
Title Siderophore-mediated cargo delivery to the cytoplasm of Escherichia coli and Pseudomonas aeruginosa: syntheses of monofunctionalized enterobactin scaffolds and evaluation of enterobactin-cargo conjugate uptake.
Journal J Am Chem Soc
Abstract The design and syntheses of monofunctionalized enterobactin (Ent, L- and D-isomers) scaffolds where one catecholate moiety of enterobactin houses an alkene, aldehyde, or carboxylic acid at the C5 position are described. These molecules are key precursors to a family of 10 enterobactin-cargo conjugates presented in this work, which were designed to probe the extent to which the Gram-negative ferric enterobactin uptake and processing machinery recognizes, transports, and utilizes derivatized enterobactin scaffolds. A series of growth recovery assays employing enterobactin-deficient E. coli ATCC 33475 (ent-) revealed that six conjugates based on L-Ent having relatively small cargos promoted E. coli growth under iron-limiting conditions whereas negligible-to-no growth recovery was observed for four conjugates with relatively large cargos. No growth recovery was observed for the enterobactin receptor-deficient strain of E. coli H1187 (fepA-) or the enterobactin esterase-deficient derivative of E. coli K-12 JW0576 (fes-), or when the D-isomer of enterobactin was employed. These results demonstrate that the E. coli ferric enterobactin transport machinery identifies and delivers select cargo-modified scaffolds to the E. coli cytoplasm. Pseudomonas aeruginosa PAO1 K648 (pvd-, pch-) exhibited greater promiscuity than that of E. coli for the uptake and utilization of the enterobactin-cargo conjugates, and growth promotion was observed for eight conjugates under iron-limiting conditions. Enterobactin may be utilized for delivering molecular cargos via its transport machinery to the cytoplasm of E. coli and P. aeruginosa thereby providing a means to overcome the Gram-negative outer membrane permeability barrier.
Volume 134(44)
Pages 18388-400
Published 2012-11-7
DOI 10.1021/ja3077268
PMID 23098193
MeSH Biological Transport Enterobactin / chemistry Enterobactin / metabolism* Escherichia coli / chemistry Escherichia coli / growth & development Escherichia coli / metabolism* Escherichia coli Infections / microbiology Humans Pseudomonas Infections / microbiology Pseudomonas aeruginosa / chemistry Pseudomonas aeruginosa / growth & development Pseudomonas aeruginosa / metabolism* Siderophores / chemistry Siderophores / metabolism*
IF 14.695
Times Cited 43
Prokaryotes E. coli NA