Enterobactin- and salmochelin-β-lactam conjugates induce cell morphologies consistent with inhibition of penicillin-binding proteins in uropathogenic Escherichia coli CFT073

Abstract

Siderophore-β-lactam conjugates based on enterobactin and diglucosylated enterobactin enter the periplasm of uropathogenic E. coli CFT073 via the FepA and IroN transporters, and target penicillin-binding proteins.

Conjugation to Enterobactin and Salmochelin S4 Enhances the Antimicrobial Activity and Selectivity of β-Lactam Antibiotics against Nontyphoidal Salmonella

“…Overall, these results are in general agreement with our recent findings for the antimicrobial activity of Ent/DGE-β-lactams 1 – 6 against uropathogenic E. coli CFT073. ,, In particular, Ent/DGE modification also enhances the antimicrobial activity of all three β-lactams against E. coli CFT073, and the conjugates show similar receptor dependence in E.…”

“…coli CFT073, and the conjugates show similar receptor dependence in E. coli CFT073 and the two Salmonella strains analyzed; however, CFT073 appears to have an additional as-yet unidentified transport mechanism for the conjugates . Taken together, these studies provide a compelling picture that employing the native tris -catecholate siderophore scaffolds Ent and DGE holds potential for narrow-spectrum antibacterial agents that target enteric bacteria.…”

“…Recently, we employed phase-contrast microscopy to examine the consequences of Ent/DGE-β-lactam treatment on the cellular morphology of E. coli CFT073 . These imaging studies revealed that sub-MIC values of Ent/DGE-Amp and Ent/DGE-Lex induced filamentation and Ent/DGE-Mem caused spheroplast formation, morphologies consistent with the β-lactams inhibiting their primary PBP targets.…”

“…Ent/DGE-β-lactam conjugates 1 – 6 harbor ampicillin (Amp), cephalexin (Lex), and meropenem (Mem) (Figure ). Amp is an aminopenicillin, Lex is a first-generation cephalosporin analog of Amp, and Mem is a “last-resort” carbapenem due to its enhanced resistance to extended-spectrum β-lactamases and cephalosporinases. − Structurally, Amp, Lex, and Mem share the same four-membered β-lactam “core” but differ by the size and composition of the ring fused to the core (Figure ). As result of these structural differences, the three β-lactams manifest different selectivity toward penicillin-binding proteins (PBPs) − and exhibit variable stability to hydrolysis.…”

Biomimetic enterobactin analogue mediates iron-uptake and cargo transport into E. coli and P. aeruginosa

“…[66][67][68][69] Ent and salmochelins also play a crucial role during infection 18,70 and they have been demonstrated to sequester iron from human transferrin. 17,19 Previously reported articial Ent analogues used for the development of siderophore drug conjugates or siderophore-based imaging tools 71,72 were based on modications at one of the catechol units 42,43,46,49,52,[73][74][75] or the natural tris-serine lactone backbone was substituted by articial moieties to generate an attachment point for payloads in the backbone of the siderophore. 48,[76][77][78] Although a co-crystal structure of [Fe-Ent] 3À with its E. coli siderophore receptors of FepA 79,80 and IroN [80][81][82] is not available, recognition of [Fe-Ent] 3À at other proteins such as FeuA, [83][84][85] VctP, 86 PfeA 69 or lipocalin-2 (ref.…”