Mimicking salmochelin S1 and the interactions of its Fe(III) complex with periplasmic iron siderophore binding proteins CeuE and VctP

Abstract

, https://www.york.ac.uk/chemistry/ Dedicated to Prof. Bernt Krebs on the occasion of his 80 th birthday Highlights  Synthesis of a mimic of the tetradentate stealth siderophore salmochelin S1  The periplasmic binding protein of Vibrio cholerae (VctP) binds the mimic strongly  VctP selects for-configured Fe(III) complexes of the mimic  VctP displays a preference for bis(catecholate) over tris(catecholate) siderophores  The role of salmochelin in iron uptake by pathogens merits further investigation

The Pneumococcal Iron Uptake Protein A (PiuA) Specifically Recognizes Tetradentate FeIIIbis- and Mono-Catechol Complexes

“…This work, along with previous work in S. aureus [30], establishes that Gram-positive pathogens exploit a mechanism of Fe III -uptake that has only previously been extensively characterized in Gram-negative organisms, notably in the intestinal pathogens, C. jejuni, Vibrio cholerae, E. coli and Salmonella enterica [43,45,63]., In C. jejuni, for example, an outer membrane receptor, CfrA, brings Fe III -Ent or Fe III -salmochelin complexes into the periplasm, where periplasm-resident esterases, e.g., Cee in C. jejuni, hydrolyze Ent to di-DHBS and DHBS monomers that coordinate Fe III and bind to CeuE for cytoplasmic transport. A similar mechanism is thought to be employed by V. cholerae VctP in processing complexes of Fe III and salmochelin hydrolysis products [43,[64][65][66][67], e.g., salmochelin-S1, a naturally occurring tetradentate siderophore produced by S. enterica in the gut [68]. In contrast, in S. enterica and E. coli, esterases reside in the cytoplasm, not the periplasm.…”

“…2). These results reveal that two Gram-positive SBPs, PiuA and SstD, exhibit Fe III -catecholate substrate specificity profiles similar to that of Gram-negative SBP CeuE [41,43].…”

“…Crystal structures of CeuE bound to a 1:1 Fe III :di-DHBS complex reveal that the two open Fe III coordination sites on one side of the bis-catecholate chelate, conserved among a subset of related SBPs, including tyrosine (Y288) buried in the binding cavity, and histidine (H227) on a flexible, surface loop, coordinate the Fe III [41]. In similar fashion, Vibrio cholerae VctP, a CeuE homolog, coordinates the Fe III -tetradentate bis-catecholate siderophore salmochelin S1, a hydrolysis product of salmochelin, a C5-glucosylated analog of Ent, using the same tyrosine and histidine residues [43]. The sequence-and structural alignments of PiuA, SstD, CeuE and VctP reveal that the ligating His and Tyr of CeuE are invariant (Fig.…”

“…In this study, we redefine S. pneumoniae PiuA as an Fe III -tetradentate catecholate binding protein rather than a hemin binding protein, as originally suggested on the basis of limited data [22,40]. Two protein-derived ligands from the central cavity between the N-and C-terminal lobes (H238 and Y300 in PiuA) complete the hexadentate, octahedral Fe III coordination geometry, largely as previously described for periplasmic SBP, CeuE, from the Gram-negative intestinal pathogen Campylobacter jejuni [41][42][43]. This finding expands the known bioavailable iron sources for Spn to include both catecholate-type siderophores and hydroxamate-type siderophores.…”

A Salmochelin S4-Inspired Ciprofloxacin Trojan Horse Conjugate

“…It was shown previously that tetradentate, diamine-linked bis(catecholates) can function as siderophore components in Trojan Horse antimicrobials, which were shown to penetrate at least the outer membrane of Gramnegative bacteria, including E. coli. 43,44 We anticipated compound 1 to possess similar iron-binding properties to the tetradentate linear enterobactin dimer 45 (Figure 2) and a previously described salmochelin S1 mimic, 46 as both feature similar 2,3-dihydroxybenzamide iron-chelating moieties attached to a 5-atomic backbone. We have previously investigated the Fe 3+ coordination chemistry of these two tetradentate bis(catecholates) by using both UV−vis and CD spectroscopy and observed rapidly equilibrating mixtures of 1:1 and 2:3 complexes, both monomers and dimers.…”